METHODS FOR CONTROLLING PAIN IN CANINES USING A
TRANSDERMAL SOLUTION OF FENTANYL
Opioids are an important part of multi-modal perioperative analgesia, especially for
moderate to severe pain. In human health, the use of opioids during and after surgery
for most soft tissue and orthopedic surgeries is considered as a standard of care and
are included in procedure specific treatment algorithms. In veterinary medicine, the
off-label use of opioids is limited by poor oral bioavailability and rapid clearance of
opioids in many animals. Products currently approved by the United States Food and
Drug Administration (FDA) for the control of postoperative pain in canines are
essentially limited to nonsteroidal anti-inflammatory drugs (NSAIDs). Off-label
opioid use in canines is primarily limited to single or repeat parenteral injections to
treat acute pain or constant rate intravenous infusions and epidural or intrathecal
injections delivered during anesthesia.
Fentanyl is a potent, full μ-opioid receptor agonist having approximately 100-fold the
analgesic properties of the opioid morphine. However, poor oral bioavailability and
rapid clearance has limited the use of fentanyl to perioperative parenteral
administrations and constant rate intravenous infusions. For example, following
intravenous (IV) administration of fentanyl citrate to canines, the elimination half-life
and clearance has been reported to range from 0.76 to 6.0 hours and 1.7 to 4.7
L/hr·kg, respectively.
Various methods to deliver fentanyl have been attempted in order to overcome these
limitations and to prolong the therapeutic duration of action. For example, methods
of transdermal application such as patches have potential advantages over oral and
parenteral administration, including non-invasive dosing, avoidance of the
gastrointestinal tract, lack of first pass metabolism, steady, continuous drug delivery
rather than a peak and trough phenomenon, potential reduction of side effects by
elimination of peaks, possible reduction of lack of effectiveness due to elimination of
troughs, and reduced dose frequency for convenience and increased compliance.
For extended use beyond the immediate postoperative period, transdermal delivery of
fentanyl in a patch formulation has been used to treat moderate to severe pain in
conscious, ambulatory canines. However, the use of fentanyl patches in canines
introduces numerous additional shortcomings, including lack of regulatory approval
in canines, slow onset of action, problems associated with maintaining patch contact
on skin, variable fentanyl delivery rate and extent, potential inadvertent fentanyl
exposure to the canine or canine owner, concern for proper control and disposal of
used patches, the possibility of diversion and illicit patch use when the canine is
discharged from the hospital, and lack of regulatory oversight and pharmacovigilance
to track adverse events in canines.
Multiple attempts to accomplish the transdermal delivery of fentanyl without a patch
have previously been unsuccessful. As a delivery method, direct drug absorption via
transdermal approaches encounters the barrier nature of the skin, thus creating
difficulties for most drugs to be delivered in this manner. For example, topical
administration of fentanyl in a pluronic lecithin organogel did not result in measurable
plasma concentration in canines.
Therefore, there exists a need for a method to use fentanyl that overcomes the
limitations of parenterally-, orally-, or patch-delivered opioids in order to benefit pain
management in veterinary medicine. It is an object of the present invention to go
some way towards meeting this need, and/or to at least provide the public with a
useful choice.
Accordingly, the present invention provides methods of using a transdermal
pharmaceutical formulation of fentanyl which exhibits desirable properties and
provides related advantages for the control of pain in canines.
The present invention demonstrates that the dermal barrier to drug permeation can be
overcome in canines by using a transdermal pharmaceutical formulation comprising
fentanyl, a penetration enhancer, and an evaporating solvent. Through deposition of
fentanyl in the stratum corneum of a canine followed by prolonged systemic
absorption, the present invention overcomes the limitations of poor oral
bioavailability as well as the short duration of action of orally and parenterally
administered fentanyl.
More specifically, in a first aspect, the present invention provides a method of
controlling pain for an effective period of time comprising transdermally
administering in a single dose to a canine in need thereof a therapeutically effective
amount of a composition comprising fentanyl, a penetration enhancer, and a volatile
liquid, wherein the composition is a solution and the transdermal administration is
applied to a dorsal interscapular or ventral location of the canine.
In a further aspect, the present invention provides a method of controlling pain for an
effective period of time comprising transdermally administering in a single dose to a
canine in need thereof a therapeutically effective amount of a composition comprising
fentanyl, octyl salicylate, and isopropanol, wherein the composition is a solution and
the transdermal administration is applied to a dorsal interscapular location of the
canine.
In another aspect, the present invention provides single dose transdermal solution
formulation for use on a canine comprising a therapeutically effective amount of
fentanyl,
a penetration enhancer selected from the group consisting of C alkyl
-18
para-aminobenzoate, C alkyl dimethyl-para-aminobenzoate, C alkyl cinnamate,
-18 5-18
C alkyl methoxycinnamate, C alkyl salicylate, octyl dimethyl-para-
-18 5-18
aminobenzoate, octyl para-methoxycinnamate, octyl salicylate, or mixtures thereof,
a volatile liquid selected from the group consisting of ethanol, ethyl
acetate, isopropanol, acetone, ethyl formate, methanol, methyl acetate, methyl ethyl
ketone, pentane, chloroform, or mixtures thereof, wherein said formulation, when
administered to a canine, provides control of pain for at least 96 hours, and is
formulated for administrating a dose of about 1 to about 5 mg of fentanyl per kg of
canine body weight.
In the description in this specification reference may be made to subject matter which
is not within the scope of the appended claims. That subject matter should be readily
identifiable by a person skilled in the art and may assist in putting into practice the
invention as defined in the appended claims.
BRIEF DESCRIPTION OF DRAWINGS
The teachings of some embodiments of the present invention will be better understood
by reference to the description taken in conjunction with the accompanying drawings,
wherein:
is a perspective view of an assembled applicator connected to a fluid delivery
device and positioned on an animal for dispensing a formulation onto the animal in
accordance with some embodiments;
is a perspective view an assembled applicator in accordance with some
embodiments;
is an end view of an outlet from the assembled applicator of taken
along line 2A;
is a perspective view of the bottom section of an applicator in accordance with
some embodiments;
is another perspective view of the bottom section of an applicator in
accordance with some embodiments;
is a cross-sectional view of the top section of an applicator of taken
along line 5A;
is a cross-sectional view of the bottom section of an applicator of
taken along line 4B;
is a cross-sectional view of the assembled applicator of taken along
line 4C;
is a perspective view of the top section of an applicator in accordance with
some embodiments;
is a cross-sectional view of a different embodiment of a top section of an
applicator;
is a cross-sectional view of a different embodiment of a bottom section of an
applicator;
is a cross-sectional view of the assembled applicator after the top section of
is ultrasonically welded with the bottom section of ;
is a cross-sectional side view of an assembled applicator of taken along
line 6;
is a cross-sectional view of another embodiment of a top section of an
applicator;
is a cross-sectional view of another embodiment of a bottom section of an
applicator;
is a cross-sectional view of the assembled applicator after the top section of
is ultrasonically welded with the bottom section of ;
is a cross-sectional view of an assembled applicator in accordance with some
embodiments;
is a magnified cross-sectional view of a portion of the assembled applicator
of and indicated by circle 8A; and
is a cross-sectional view of the assembled applicator of showing a
plane passing through the joint.
This invention provides methods of controlling pain in a canine comprising
transdermally administering a composition comprising fentanyl, a penetration
enhancer, and a volatile liquid, wherein the composition is a solution. The invention
also provides a single unit dose of the composition.
The present invention provides several advantages compared to fentanyl administered
to canines in a patch formulation. First, the present invention achieves minimally
effective plasma concentrations within hours of application and can be administered
shortly before surgery to provide pre-emptive analgesia of a canine. Second, the
present invention achieves a longer duration of action. Dependent upon the individual
canine’s responsiveness to fentanyl, a single dose of a therapeutically effective
amount of the present invention could last several days. Third, because the present
invention is a transdermal solution and not a device, the invention does not require the
maintenance of skin contact in canines to maintain appropriate fentanyl absorption.
Fourth, the present invention is administered on a per kilogram basis that results in
dose-proportional pharmacokinetics, thus overcoming problems with variable rate and
extent of fentanyl delivered to canines in a patch formulation. Fifth, the present
invention limits inadvertent exposure to the canine or the canine owner because
fentanyl is rapidly sequestered in the stratum cornuem immediately after drying, and
no fentanyl reservoir is present. Finally, without a fentanyl reservoir, diversion and
illicit use of the present invention, as well as disposal concerns outside the control of a
licensed veterinarian, are minimized.
The methods according to the present invention utilize administration of a
composition to a canine for control of pain. As used herein, the terms “control of
pain” or “controlling pain” refer to preventing, minimizing, or eliminating pain in a
canine. As used herein, the term “pain” represents all categories of pain, including
traumatic pain resulting from tissue injury, post-surgical pain, burn pain,
inflammatory pain, pain associated with disease (such as cancer, infection,
osteoarthritis, rheumatoid arthritis, or other type of arthritis), pain associated with
nerve damage, neuropathy, and other forms of neuralgic, neuropathic and idiopathic
pain syndromes, and specific organ or tissue pain, such as ocular and corneal pain,
bone pain, heart pain, skin pain, visceral (kidney, gall bladder, gastrointestinal, etc.)
pain, joint pain, dental pain, and muscle pain. The term “pain” also includes pain of
varying severity, i.e. mild, moderate and severe pain, as well as acute and chronic
pain.
In the present invention, the methods utilize administration of a composition to a
canine for control of pain during an effective period of time. As used herein, the term
“effective period of time” comprises a period of at least 24 hours. In some
embodiments, an effective period of time comprises a period of at least 24 hours, a
period of at least 48 hours, a period of at least 72 hours, a period of at least 96 hours,
or a period of at least 7 days.
The composition administered according to the present invention comprises fentanyl,
a penetration enhancer, and a volatile liquid. Fentanyl is a full μ-opioid receptor
agonist and is also known by chemical names such as N-Phenyl-N-[1-(2-phenylethyl)-
4-piperidinyl]propanamide, N-(1-phenethylpiperidyl)-propionanilide, or N-(1-
phenethylpiperidinyl)-N-phenylpropionamide. The chemical structure of fentanyl
is:
As used herein, the term “fentanyl” refers to fentanyl base, pharmaceutically
acceptable salts of fentanyl, or other salts of fentanyl. The term “pharmaceutically
acceptable salt” refers to an addition salt that exists in conjunction with the acidic or
basic portion of fentanyl. Such salts include the pharmaceutically acceptable salts
listed in HANDBOOK OF PHARMACEUTICAL SALTS: PROPERTIES,
SELECTION AND USE, P. H. Stahl and C. G. Wermuth (Eds.), Wiley-VCH, New
York, 2002 which are known to the skilled artisan. Pharmaceutically acceptable salts
of an acid addition nature are formed when fentanyl and any of its intermediates
containing a basic functionality are reacted with a pharmaceutically acceptable acid.
Pharmaceutically acceptable acids commonly employed to form such acid addition
salts include inorganic and organic acids. Pharmaceutically acceptable salts of a base
addition nature are formed when fentanyl and any of its intermediates containing an
acidic functionality are reacted with a pharmaceutically acceptable base.
Pharmaceutically acceptable bases commonly employed to form base addition salts
include organic and inorganic bases.
In addition to pharmaceutically acceptable salts, other salts are included in the present
invention. They may serve as intermediates in the purification of compounds or in the
preparation of other pharmaceutically-acceptable salts, or are useful for identification,
characterization or purification.
As used herein, the term “penetration enhancer” refers to a chemical that improves the
transport of drugs across the skin barrier. Penetration enhancers according to the
present invention may act by disrupting the packing of skin lipids and thus altering the
barrier nature of the stratum corneum, by changing the partitioning behavior of the
drug at the stratum corneum-viable epidermis interface, or by affecting the
thermodynamic activity of the drug. The penetration enhancers can be of low toxicity
to the skin and are typically promoters of percutaneous absorption. In some
embodiments, the penetration enhancer is a lipophilic chemical. Penetration
enhancers and uses thereof are described, for example, in U.S. Patent Nos. 6,299,900,
6,818,226, and 6,916,486.
The penetration enhancers according to the present invention are particularly suitable
for transdermal delivery of analgesics through the skin of an animal such as a canine.
A number of penetration enhancers are known in the art. In some embodiments,
penetration enhancers include fatty acids, fatty acid esters, fatty alcohols, glycols and
glycol esters, 1,3-dioxolanes and 1,3-dioxanes, macrocyclic ketones containing at
least 12 carbon atoms, oxazolidinones and oxazolidinone derivatives, alkyl(N,N-
disubstituted amino)-alkanoate esters, (N,N-disubstituted amino)-alkanol alkanoates,
sunscreen esters, and mixtures thereof. In some embodiments, penetration enhancers
are selected from the group consisting of oleic acid, oleyl alcohol,
cyclopentadecanone (CPE-218™), sorbitan monooleate, glycerol monooleate,
propylene glycol monolaurate, polyethylene glycol monolaurate, 2-n-nonyl 1,3-
dioxolane (SEPA™), dodecyl 2-(N,N-dimethylamino)-propionate (DDAIP) or its salt
derivatives, 2-ethylhexyl 2-ethylhexanoate, isopropyl myristate, dimethyl isosorbide,
4-decyloxazolidinonone (SR-38™, TCPI, Inc.), 3-methyldecyloxazolidinon
one, octyl dimethyl-para-aminobenzoate, octyl para-methoxycinnamate, octisalate,
and mixtures thereof.
In some embodiments, penetration enhancers can be sunscreen esters such as the
compounds described in U.S. Patent Serial Number 6,299,900. For example, the
compounds can be safe skin-tolerant ester sunscreens of formula:
1 3 4
wherein R is hydrogen, lower alkyl, lower alkoxy, halide, hydroxy or NR R ;
R.sup. is long chain alkyl;
3 4 3 4
R and R are each independently hydrogen, lower alkyl or R and R together
with the nitrogen atom to which they are attached form a 5- or 6-membered
heterocyclic ring;
n is 0 or 1; and
q is 1 or 2.
In some embodiments, penetration enhancers are esters having a long chain alkyl
para-aminobenzoate, long chain alkyl dimethyl-para-aminobenzoate, long chain alkyl
cinnamate, long chain alkyl methoxycinnamate or long chain alkyl salicylate. In
some embodiments, penetration enhancers are selected from the group consisting of
octyl dimethyl-para-aminobenzoate ("Padimate O"), octyl para-methoxycinnamate,
octyl salicylate (also known as octisalate) or mixtures thereof. In one embodiment,
the penetration enhancer is octyl salicylate.
As used herein, the term “volatile liquid” refers to any pharmacologically suitable
liquid composition known in the art. For example, a volatile liquid may be readily
vaporizable at low temperatures or tends to evaporate rapidly. Once applied to the
skin, rapid evaporation of volatile liquids according to the present invention can result
in super-saturation of other ingredients of the composition. In some embodiments,
volatile liquids according to the present invention include safe skin-tolerant solvents.
In some embodiments, the volatile liquid is a lower alkyl alcohol or a mixture of such
alcohols. In some embodiments, the volatile liquid selected from the group consisting
of ethanol, ethyl acetate, isopropanol, acetone, ethyl formate, methanol, methyl
acetate, methyl ethyl ketone, pentane, chloroform, or mixtures thereof. In other
embodiments, the volatile liquid is ethanol or isopropanol or mixtures thereof. In one
embodiment, the volatile liquid is isopropanol.
The methods according to the present invention utilize administration of a
composition wherein the composition is in a solution. In some embodiments of the
present invention, the composition comprises fentanyl, a penetration enhancer, and a
volatile liquid at various amounts based on a weight per volume of the solution. In
some embodiments, the composition comprises on a weight basis from about 0.1 to
about 10% of fentanyl, from about 0.1 to about 10% of the penetration enhancer, and
from about 80% to about 99.8% of the volatile liquid. In another embodiment, the
composition comprises on a weight basis from about 1 to about 10% of fentanyl, from
about 1 to about 10% of the penetration enhancer, and from about 80% to about 98%
of the volatile liquid. In another embodiment, the composition comprises on a weight
basis from about 2 to about 8% of fentanyl, from about 2 to about 8% of the
penetration enhancer, and from about 84% to about 96% of the volatile liquid. In
another embodiment, the composition comprises on a weight basis from about 3 to
about 7% of fentanyl, from about 3 to about 7% of the penetration enhancer, and from
about 86% to about 94% of the volatile liquid. In yet another embodiment, the
composition comprises on a weight basis from about 1 to about 5% of fentanyl, from
about 1 to about 5% of the penetration enhancer, and from about 90% to about 98% of
the volatile liquid. In another embodiment, the composition comprises on a weight
basis about 5% of fentanyl, about 5% of the penetration enhancer, and about 90% of
the volatile liquid.
Furthermore, the methods according to the present invention utilize administration of
a composition wherein the administration is a transdermal administration. As used
herein, the term “transdermal” has its ordinary meaning in the art and refers to
passage of an agent across at least one skin layer of an animal, for example a canine.
Further, the term “transdermal” is used co-terminously with the term “topical” in
describing the application of agents to the skin. Both terms “topical” and
“transdermal” are used herein in the broadest sense to refer to administration of a drug
to the skin surface of an animal so that the drug passes through the skin layer. Unless
otherwise stated or implied, the terms topical drug delivery and transdermal drug
delivery are used interchangeably. From a strict drug-delivery perspective,
“transdermal” is sometimes used to refer only to systemic delivery through the skin
whereas “topical” requires only delivery into or on the skin for local effect. The
invention described in this specification is equally applicable to both transdermal and
topical modes of delivery, and is described here as “transdermal” only for
convenience. The methods according to the present invention may utilize transdermal
administration of the composition wherein the composition is desirably not a
transdermal patch.
In carrying out the methods of this invention, the amount of fentanyl in the
composition is adequate to achieve a therapeutic effect. As used herein, the term
“therapeutically effective amount” refers to an amount which gives the desired benefit
to a canine and includes both treatment and prophylactic administration. The amount
will vary from one canine to another and will depend upon a number of factors,
including the overall physical condition of the canine and the underlying cause of the
condition to be treated.
The amount of fentanyl used for the controlling pain gives an acceptable rate of
change and maintains desired response at a beneficial level. A therapeutically
effective amount of the composition used in the methods of this invention may be
readily ascertained by one of ordinary skill in the art using publicly available
materials and procedures. In one embodiment of the present invention, the
therapeutically effective amount of fentanyl to be delivered can be quantified by
determining milligrams of fentanyl per kilogram of canine body weight. In some
embodiments, the therapeutically effective amount of fentanyl in the composition can
be present in an amount of between about 0.01 and about 10 milligrams per kilogram
of canine body weight. In another embodiment, the therapeutically effective amount
of fentanyl in the composition can be present in an amount of between about 0.1 and
about 10 milligrams per kilogram of canine body weight. In yet another embodiment,
the therapeutically effective amount of fentanyl in the composition can be present in
an amount of between about 1 and about 5 milligrams per kilogram of canine body
weight. In some embodiments, the therapeutically effective amount of fentanyl in the
composition can be present in an amount of between about 2 and about 4 milligrams
per kilogram of canine body weight. In some embodiments, the therapeutically
effective amount of fentanyl in the composition can be present in an amount of
between about 2 and about 3 milligrams per kilogram of canine body weight. In one
embodiment, the therapeutically effective amount of fentanyl present in the
composition is about 2.7 mg/kg. In one embodiment, the therapeutically effective
amount of fentanyl present in the composition is about 2.6 mg/kg.
In one embodiment, the composition according to the present invention comprises on
a weight basis about 5% of fentanyl in a solution (i.e., 50 mg/mL) and the
therapeutically effective amount of fentanyl present in the composition is about 2.7
mg/kg. In this embodiment, the methods of the present invention can be
transdermally administered to a canine according to the doses shown in Table 1.
Table 1. Doses of the Composition of the Present Invention Based on Canine
Body Weight
In some embodiments, the therapeutically effective amount is an amount sufficient to
achieve a minimum effective plasma concentration (MEC). Generally, MEC has been
defined as the minimum plasma concentration of an analgesic that is sufficient to
prevent a patient from requesting a supplementary analgesic. The MEC of fentanyl in
humans has been established in a population of adults undergoing abdominal surgery.
Following surgery, fentanyl was delivered at a basal IV infusion rate of 20 µg/hr with
microgram on demand boluses self administered by the patient when pain became
unacceptable. A blood sample collected just prior to the patient administering
additional analgesia was considered the MEC. Over 48 hours, the MEC ranged from
0.23 to 1.18 ng/mL (mean 0.63 ng/mL) and remained relatively constant within
individual patients over the 48-hour study period. Thus, in humans where pain was
alleviated at 0.2 ng/mL this remained constant over time as well as for those where
pain was alleviated with 1.18 ng/mL. This suggests a 6-fold range of minimally
effective fentanyl concentrations dependent on individual responsiveness.
Canines cannot request their own supplementary analgesia, thus quantifying the true
MEC remains difficult and depends on an observer making inferences from presumed
pain related behaviors displayed by canines. Despite these limitations, behavior-
based studies have evaluated analgesia and plasma fentanyl concentration in canines
to approximate analgesia and drug concentrations. The results support the notion that
the MEC in canines likely overlaps with that observed in humans. Studies in canines
undergoing various surgeries have shown that fentanyl concentrations ranging from
0.4-1.28 ng/ml were effective in controlling pain. A review and analysis of all studies
conducted with fentanyl patches in canines suggests that a mean plasma fentanyl
concentration of 0.6 ng/ml is effective at providing analgesia.
In some embodiments of the present invention, pain is associated with a surgery
performed or to be performed on the canine. In one embodiment of the present
invention, the composition is administered between two to four hours prior to a
surgery performed or to be performed on a canine. In one embodiment, the surgery
performed or to be performed on the canine is an orthopedic surgery. As used herein,
the term “orthopedic surgery” refers to a surgical procedure pertaining to the
preservation or restoration of the function of the musculoskeletal system, its
articulations, and associated structures.
In another embodiment, the surgery performed or to be performed on the canine is a
soft tissue surgery. As used herein, the term “soft tissue surgery” refers to a surgical
procedure pertaining to the preservation or restoration of the function of muscle, fat,
fibrous tissue, blood vessels, or other supporting tissue of the body, for example
tendons, ligaments, fascia, skin, nerves, or synovial membranes.
In another embodiment, the surgery performed or to be performed on the canine is
associated with cranial cruciate rupture. In one embodiment, the surgery associated
with cranial cruciate rupture is a stabilization surgery.
In one embodiment of the present invention, the composition is contained in a
multiple-dose vial prior to administration. The multiple-dose vial containing the
composition of the present invention can be made of glass, plastic, or other material.
The composition may be administered as a multiple dose regimen. In one
embodiment, the multiple dose regimen is a time period of approximately 14 days. In
another embodiment, the multiple dose regimen is a time period of approximately one
month. In yet another embodiment, the multiple dose regimen is a time period of
approximately two months. In another embodiment, the multiple dose regimen is a
time period of approximately three months. In yet another embodiment, the multiple
dose regimen is a time period of approximately four months.
In the present invention, the composition is administered as a single dose. In another
embodiment of the present invention, the composition is administered as a single unit
dose. As used herein, the term “unit dose” is a discrete amount of the composition
comprising a predetermined amount of fentanyl. The amount of fentanyl is generally
equal to the dosage of fentanyl which would be administered to a canine or a
convenient fraction of such a dosage such as, for example, one-half or one-third of
such a dosage.
According to the methods of the present invention, the terms “single dose” and
“single unit dose” include embodiments wherein the composition can be
transdermally administered as a single application and administered as multiple
applications. In one embodiment, a single dose or single unit dose of the composition
can be transdermally administered to a canine in a single application at one location
on the canine’s skin. In another embodiment, a single dose or single unit dose of the
composition is transdermally administered to a canine in a single application at one
location on the canine’s skin, wherein the single application is about 0.5 mL of a
solution of the composition. In one embodiment, a single dose or single unit dose of
the composition can be transdermally administered to a canine in multiple
applications at a single location on the canine’s skin. In another embodiment, a single
dose or single unit dose of the composition is transdermally administered to a canine
in multiple applications at a single location on the canine’s skin, wherein each
application has up to about 0.5 mL of a solution of the composition. In one
embodiment, a single dose or single unit dose of the composition can be transdermally
administered to a canine in multiple applications at more than one location on the
canine’s skin. In another embodiment, a single dose or single unit dose of the
composition is transdermally administered to a canine in multiple applications at more
than one location on the canine’s skin, wherein each application has up to about 0.5
mL of a solution of the composition. In embodiments wherein multiple applications
of the composition are utilized, the multiple applications can be administered to the
canine over a reasonable duration of time.
In one embodiment of the present invention, the composition is transdermally
administered to a canine at a dorsal location of the canine. According to the methods
of the present invention, the term “dorsal” has its ordinary meaning and as used herein
refers to the direction to the rear of the spine of a canine, i.e., outwardly through the
canine’s back. In one embodiment of the present invention, the composition is
transdermally administered to a canine at a ventral location of the canine. According
to the methods of the present invention, the term “ventral” has its ordinary meaning
and as used herein refers to the direction to the front of the spine of a canine, i.e.,
frontwards through the canine’s body.
The compositions of the present invention include those that also optionally contain
one or more other active ingredients, in addition to fentanyl. As used herein, the term
“active ingredient” or “therapeutic ingredient” refers to a therapeutically active
compound, as well as any prodrugs thereof and pharmaceutically acceptable salts,
hydrates, and solvates of the compound and the prodrugs. Other active ingredients
may be combined with fentanyl and may be either administered separately or in the
same pharmaceutical formulation. The amount of other active ingredients to be given
may be readily determined by one skilled in the art based upon therapy with fentanyl.
In one embodiment of the methods according to the present invention, a transdermal
dispensing apparatus can be used to administer the composition to a canine. In one
embodiment, the transdermal dispensing apparatus is an applicator for dispensing a
formulation herein described to an animal. An example of a transdermal dispensing
apparatus is described, for example, in PCT Patent Application No.
and in U.S. Patent Application No. 12/581,658.
The applicator comprises a housing including first and second sections coupled
together, the first and second sections defining a channel therebetween that includes at
least one outlet; a hub integral with the first section and extending therefrom, the hub
defining a conduit; and a bent path connecting the conduit to the channel. In
accordance with this embodiment, the conduit, the bent path and the channel are
fluidly connected.
In accordance with still another aspect of the present invention, a method is provided
for dispensing the formulation herein described from an applicator of the type having
a housing including first and second sections coupled together to form a channel and a
hub extending from the housing, the hub being attachable to a syringe. The method
comprises attaching the hub to a syringe containing a formulation; placing an outlet of
the applicator on or near the animal; causing the formulation to be released from the
syringe into the applicator; passing the formulation through the hub, through a bent
path and then into the channel; and dispensing the formulation from the applicator
through the outlet.
The applicators described herein can be particularly useful for transdermally
delivering doses of controlled veterinary substances (e.g., fentanyl) to the coat and
skin of an animal, which may include a canine. In certain exemplary embodiments,
the drug delivery device includes an applicator device or tip that is compatible with a
standard luer lock syringe and consists of a housing that allows the formulation to be
spread over a surface area of' the animal's skin or coat. To accomplish this, the
applicator body includes one or more outlets that are in the form of legs or tines
configured to penetrate the fur of the animal and thereby deliver the drug directly to
the animal's skin or coat. In certain aspects, the outlet(s) further includes a pair of
spaced prongs or feet that extend from its distal end, thereby allowing the formulation
to be freely dispensed onto the surface of the animal. More particularly, because the
spaced feet extend outwardly from the distal end of applicator, they are the only
structural portion of the assembled applicator that directly contact and seal against the
surface of the animal. Moreover, since the outlet opening is positioned between the
spaced apart prongs and in such a manner that it does not directly contact or seal
against the surface of the animal during a dispensing operation, the formulation is able
to be freely dispensed and spread onto the animal without being physically impeded
or interrupted.
A non-limiting illustration of an assembled applicator coupled to a fluid delivery
device in accordance with the present teachings is shown in More
specifically, depicts a perspective view of a user 100 dispensing a formulation
herein described onto an animal 102. In accordance with this exemplary and non-
limiting illustration, a fluid delivery device 104 containing the formulation is
releasably attached to an applicator device 106 and then placed on or near the surface
of the animal 102. While this illustrative embodiment shows the fluid delivery device
104 as a standard syringe, it should be understood and appreciated herein that delivery
of the formulation may be accomplished by any known fluid delivery device or
connector that is releasably attachable to the applicator device 106 and having a
reservoir for holding and/or storing the formulation to be dosed or dispensed. Other
such non-limiting and illustrative fluid delivery devices that may also be used include,
but are not limited to, syringes, catheters, hubbed needles, IV tubes and cylinder fluid
delivery devices.
As will be explained in detail below, the applicator devices 106 generally consist of at
least two parts or halves (i.e., sections 114 and 214) that are coupled or assembled
together to form the applicator structure. Unlike many other traditional applicator
devices that consist of either one applicator part or two structurally complementary
parts, the devices include two sections 114, 214 that are somewhat complementary in
terms of structure, yet specifically shaped in such a manner that once assembled, the
formulation can be dispensed therefrom without experiencing much associated
leakage or residual buildup. More particularly, the sections 114, 214 are structurally
shaped such that when they are coupled together, the formulation is discouraged from
leaking out of the applicator body. In addition, the structural orientation of the
dispensing passageway that is created between the first and second sections is shaped
in such a manner that substantially all of the formulation is encouraged from being
dispensed from the applicator device during a dispensing operation. As such, it
should be understood and appreciated herein that at least some of the unexpected
advantages are influenced by the resultant shape and configuration of the dispensing
passageway that is formed by the assembled applicator sections.
Moving now to a perspective view of a fully assembled applicator 106 is
shown. The applicator 106 includes a housing or body 108 defining an inlet hub 110
and an outlet 112. As will be explained in more detail below, the inlet hub 110 is
attachable to the drug delivery device 104 during a dispensing operation, whereas the
outlet portion 112 is capable of penetrating the fur of an animal so that the
formulation can be appropriately dispensed therefrom and onto the surface of the
animal. The applicator 106 can be made from polyethylene, polypropylene, polyvinyl
acetate, polystyrene, polyethylene terephthalate, polybutylene terephthalate, and
polytetrafluoroethylene, and the like.
In terms of assembly, the applicator 106 comprises first and second sections or faces
(114, 214) that are coupled or assembled together to form the housing 108. As shown
in FIGS. 3 and 4, the first section 114 includes a top surface 117, a bottom surface
118, a back edge 119 integral with the inlet hub 110 and first and second sides 120,
122, the first and second sides being defined by a pair of substantially parallel outlet
ends or legs 123, 125 that extend from and partially surround a substantially flat
middle section 121 that is disposed between the first and second sides 120, 122.
Extending upwardly from the top surface 117 of the first preassembled section 114
and positioned substantially along its outer periphery are a pair of ribs 124, 126 that
are spaced from each other in a parallel fashion. In certain exemplary embodiments,
the ribs 124, 126 are trapezoidal shaped and have four sides with the top and bottom
sides being parallel to one another. In accordance with this exemplary embodiment,
the spaced ribs 124, 126 have a groove or channel 127 that is formed therebetween.
In certain aspects, the groove 127 is sunken or depressed below the top surface 117 of
the first section, thereby creating a channel for delivering the formulation to the outlet
ends 123, 125 and ultimately onto the animal. To achieve the sunken channel
formation, the groove 127 is provided as a depression below the surface 117 and has a
substantially semi-circular shape. A more detailed and non-limiting exemplary
illustration of this semi-circular geometry can be seen with reference to ,
which illustrates a cross-sectional view of the first section 114 taken along line 4B of
While this exemplary illustration shows the groove or channel 127 being
semi-circular in shape, it should be understood and appreciated herein that any known
geometric shape useful for establishing a channel that permits a fluid or other such
liquid agent to travel therethrough is envisioned and can be used.
As explained above, it should be understood and appreciated herein that the first
preassembled section 114 is configured to be coupled to and molded with the second
preassembled section 214 to form a fully assembled applicator device 106. In
addition, the channel or groove 127 that is formed between the ribs 124 and 126 is
positioned and shaped in such a manner that a fluid passageway or conduit for
dispensing the formulation is formed between the fluid delivery device 104 and the
dispensing end of the outlet 112 once section 114 is coupled to and molded with
section 214.
Moving now to the second preassembled section 214 has a shape that is
substantially similar to and which complements the first preassembled section 114;
however, it does not have a corresponding inlet hub portion or a rib and groove
arrangement like that of the first section 114. Instead, the second section 214 includes
a top surface 217, a bottom surface 218, and a back edge 219 having a rounded
portion 221 that is substantially centrally located along the back edge 219 and is
configured to substantially align with the inlet hub 110 portion of the first section
during assembly. To achieve this alignment, the inlet hub 110 has a flat end portion
110a that is complementarily shaped to and configured to seamlessly mate with a flat
end portion 214a of the second section 214. The second preassembled section 214
also includes first and second sides 220, 222 that are defined by a pair of substantially
parallel outlet ends or legs 223, 225 that extend from and partially surround a
substantially flat middle section 227 that is disposed between the first and second
sides 220, 222. Extending outwardly from the bottom surface 218 of the second
section and positioned substantially along its outer periphery is a ledge or energy
director 224 that is formed by a pair of spaced grooves 226, 228. A more detailed and
non-limiting exemplary illustration of this geometric configuration can be seen with
reference to , which illustrates a cross-sectional view of the second section
214 taken along line 4A of
During assembly of the applicator 106, the pair of spaced ribs 124, 126 of the first
preassembled section 114 are configured to substantially align with (and mate) the
spaced grooves 226, 228 of the second section 214, thereby forming the passageway
or channel 127 for dispensing the formulation. In accordance with certain exemplary
embodiments, the passageway 127 is asymmetric relative to a seamless joint 113 that
attaches the first and second sections 114, 214 together. A fully assembled view of
the first and second sections 114, 214 aligned and mated together can be seen in
FIGS. 4C and 6, which respectively depict a cross-sectional view of the assembled
applicator 106 from taken along line 4C and a cross-sectional side view of the
assembled applicator 106 from taken along line 6.
As can be seen particularly in , after the first and second sections are welded
together, the spaced ribs 124, 126 meld into grooves 226, 228 so that a seamless joint
113 is formed between the two faces 114, 214, and the channel 127 is formed
therebetween. In particular, a substantially flat portion of the channel 127 is defined
by the seamless joint 113. Once fully assembled, the channel 127 creates a fluid
passageway between the inlet hub 110 and the one or more outlets 112. As shown in
, the distal end 112a of the applicator's outlet is open (see reference numeral
127a) so the formulation can be emptied from channel 127 during a dispensing
application.
In another embodiment, the first and second preassembled sections 114, 214 can be
coupled together to form an assembled applicator 106 by various known plastic
molding and manufacturing methods. However, in certain aspects, the applicator 106
is formed by ultrasonically welding the first and second preassembled sections 114,
214 together. In accordance with this exemplary and non-limiting embodiment, the
first and second preassembled sections 114, 214 are mated and aligned together as
explained above, and an ultrasonic weld, for instance along the ledge 224, is initiated
to thereby cause the sections to seamlessly meld or join together. As is readily known
and appreciated by those of skill in the plastics manufacturing and welding arts, the
process of ultrasonically welding two plastic parts together along an energy director
that has been formed into one of the preassembled parts allows a bond to be formed
that is tensile and resists the tendency of forces to tear the bond apart. Specifically,
the ultrasonic energy melts the point contact between the parts, thereby creating a
seamless joint. Moreover, these types of welds can typically be strengthened by
either increasing the weld depth, or increasing the size of the energy director to
provide a larger weld area. Accordingly, it should be understood and appreciated
herein that the precise shapes and sizes of the preassembled components described
herein are not essential, particularly as a skilled artisan would understand how to
maximize the size and shapes of the components to achieve the best welded result for
the specific dispensing applicator device to be assembled.
There are, however, advantages to the embodiment of the applicator 106 illustrated in
FIGS. 4A, 4B, and 4C. In particular, the structure of the first section 114 and second
section 214 is advantageous in forming a substantially semi-circular channel 127 that
encourages a formulation to be dispensed therethrough while leaving only a minimal
amount of residual remaining in the channel after use. One reason for this is because
the weld path, i.e., seamless joint 113, is disposed close to the fluid path, i.e., channel
127. Another reason is because the channel 127 has a substantially flat portion, the
ribs 124, 126 can be positioned closer to one another. As such, the channel 127 can
be smaller thereby reducing the overall volume of the channel, which effectively
reduces the amount of residual formulation remaining in the channel after dispensing
the agent therethrough.
Another advantage with the illustrated embodiment of the applicator 106 is the shape
of the grooves 226, 228 and the ledge 224 in the second section 214. Each groove is
substantially V-shaped and the ledge 224 is substantially flat, as shown in ,
such that when the first and second preassembled sections 114, 214 are mated and
aligned together there is very little, if any, flash remaining in the channel 127. During
ultrasonic welding, for example, the ultrasonic energy melts the energy director, i.e.,
ledge 224 , to form the joint 113 between the first and second sections 114, 214. In
, after the first section 114 and second section 214 are welded together, the
channel 127 is formed without flash forming in the channel. Flash can disrupt or
obstruct the flow of the formulation passing through the channel 127. Larger amounts
of residual fluid can remain in the channel after the formulation is dispensed when
flash is present in the channel 127. By reducing or eliminating flash, the channel 127
maintains a substantially semi-circular shape therethrough, which as described above
reduces the amount of residual formulation remaining in the channel after use.
This is not, however, the case with differently shaped grooves and/or ledge in the
second section. In , for example, a different embodiment of a second section
514 having a top surface 517 and bottom surface 518 is shown. In addition, a
different cross-section of the second section 514 is illustrated in which grooves 526,
528 are trapezoidal. The trapezoidal grooves 526, 528 are complementary to the
trapezoidal ribs 124, 126 of the first section 114 (). An energy director or
ledge 524 of the second section 514 is substantially flat and therefore similar to the
ledge 224 in . As can be seen in , after the first and second sections
are welded together, the spaced ribs 124, 126 meld into grooves 526, 528 so that a
seamless joint 113 is formed between the two faces 117, 518, and the channel 127 is
formed therebetween. Unlike the semi-circular channel 127 shown in ,
however, the mating of the trapezoidal grooves 526, 528 with the trapezoidal ribs 126,
128 produces flash 540 which fills a portion of the channel 127. The flash 540
reduces the size of the channel 127 such that the channel 127 no longer is semi-
circular. One reason flash is produced in the channel is due to the difficulty of
welding the trapezoidal grooves 526, 528 and the trapezoidal ribs 126, 128.
In , another embodiment of a second section 714 having a top surface 717 and
bottom surface 718 is shown. Moreover, the second section 714 includes grooves
726, 728 which are V-shaped and therefore similar to the grooves 226, 228 of . The second section 714, however, also includes an energy director or ledge 724
that is not flat. Instead, the ledge 724 is pressed above the bottom surface 718 and has
a semi-circular cross-section. The shape of the ledge 724 complementarily
corresponds with the semi-circular channel 127 of the first section 114 shown in . As can be seen in , as the first and second sections are welded together,
the spaced ribs 124, 126 meld into grooves 726, 728 so that a seamless joint 113 is
formed between the two faces 117, 718, and the channel is formed therebetween. The
channel 127 formed between the first and second sections has a substantially circular
crosssection, but flash 740 forms in the channel thereby inhibiting flow therethrough.
Flash is produced in the channel 127 due to the difficulty of welding the two sections
together. As can be seen in , for example, the ledge 724 is no longer
substantially flat. In particular, there is very little material along the ledge 724 that
contacts the first section 114 for ultrasonically welding the two sections together.
Thus, to ensure a proper bond is formed to hold the first and second sections together,
flash fills along the edges of the channel 127. Therefore, while it should be
understood and appreciated herein that the precise shapes and sizes of the
preassembled components described herein are not essential, it is advantageous for the
preassembled components to comprise shapes and sizes that facilitate little to no flash.
A more detailed description of the various parts of the applicator 106 will now be
provided. As is particularly shown in FIGS. 6, 8, 8A and 8B, the inlet hub 110 is
fluidly connected to the first section 114 by way of a path 128 that is disposed
between a pair of openings 130, 132. As should be understood and appreciated
herein, the fluid connection between the inlet hub 110 and the first section 114 defines
a conduit for receiving the formulation from the fluid delivery device 104 to the
groove or channel 127. More particularly, the inlet hub 110 has a first opening 130
that is disposed at the proximal end 211 of the inlet hub 110 and functions as an
insertion hole for receiving the dispensing end of the fluid delivery device (such as
device 104 in . Opposite the first opening 130 is a second opening 132, which
is fluidly connected to the groove or channel 127 of the housing 108. As such, the
inlet hub 110 is designed to functionally form an opening for the fluid delivery device
104 so that the formulation can be easily and conveniently dispensed therefrom.
The inlet hub 110 has a pair of winged ears 111 adapted to lock to the fluid delivery
device (not shown). More particularly, the fluid delivery device (e.g., device 104 in
is inserted into first opening 130 and securely attached to inlet hub 110 by any
fastening means known in the art. Exemplary connection means include, but are not
limited to, luer lock connections. Luer lock connections are well known in the field
of medicine and are typically used for coupling a syringe or other such liquid or gas
source to a catheter line or medical device. Moreover, as will be appreciated and
understood by those skilled within the relevant art, the luer connectors may be female
or male in orientation and may function as luer-locking devices, luer-slip connection
devices or the like. In accordance with some specific aspects, the luer lock
connection is achieved between the fluid delivery device 104 and the winged ears 111
of the inlet hub 110.
As can be appreciated from the discussion above, the flow path 128 undergoes a
significant reduction in diameter along the direction of fluid flow (i.e., from the inlet
hub 110 to the distal end 112a of the outlet 112). This is necessary to adapt the
applicator for connection to larger fluid delivery devices at the end of hub 110 on the
one hand, and on the other hand to the very small channel 127 through which the fluid
is moved before being dispensed from the outlet(s) 112. This reduction in diameter
causes significant pressure within path 128, which in turn can cause leakage if there
are any weak or vulnerable points such as weld seams along path 128. To address
these structural issues, path 128 is bent or shaped such that it is circuitous in nature -
i.e., is not a direct route between the first and second openings 130, 132 and changes
direction one or more times. In this manner, path 128 is formed entirely within a
single section, section 114, of the applicator, which avoids weld seams being present
for any of the structure that defines path 128. With reference to , for example,
the interface between the first and second sections, i.e., joint 113 (, defines a
plane 800 that passes therethrough. As shown in this illustrative embodiment, the
path 128 is offset from the plane 800. By locating the flow path in one section of the
applicator (as opposed to two sections defining a flow path therebetween) and
consequently eliminating all weld seams within the area defined by the flow path 128,
the occurrence of leakage as the fluid flows between the fluid delivery device 104 and
the channel 127 is substantially reduced, if not eliminated.
The structure defining path 128 can be appreciated with reference to FIGS. 8 and 8A,
wherein the conduit defined by the inlet hub 110 includes a short hollow cylindrical
chamber 134 that is disposed between the first and second openings 130, 132 and
terminates substantially centrally into the channel 127 at the second opening 132.
Chamber 134 is typically designed such that it is dimensionally non-uniform (i.e.,
varies in width and height between the first opening 130 and the second opening 132).
According to this aspect, the internal diameter of the chamber 134 changes to achieve
the reduction in diameter and configuration needed to maintain path 128 within a
single section 114 of the applicator. As mentioned above, it has been found that this
configuration avoids leakage of the formulation as it flows between the fluid delivery
device and the channel.
In certain aspects, one or more tubes or other such enclosed tubular structures can be
internally incorporated into the structural design of the present applicators. For
instance, to avoid any associated leakage that may occur around the connection
between the fluid delivery device and the applicator or along the joint 113 that is
formed between the first and second molded sections 114, 214, one or more chambers
can be internally added into the inlet hub 110 portion and/or within the formed
channel 127 of the applicator body. While such additional structure can be
incorporated into any of the embodiments without straying from the present teachings,
it should be understood and appreciated herein that such structures are not required.
More particularly, it has been found that utilizing the bent path orientation and
complementary structural design of the applicator sections makes it possible to
achieve a tubeless design that is not only free of manifolds, but is also capable of
operating without resultant leakage.
In certain exemplary embodiments, the chamber 134 contains ridges, ledges, or other
such similar structures to cause a bending configuration and stepped down diameter of
the path 128. In still other aspects, the path 128 is positioned below the seamless joint
113 that is formed between the first and second sections 114, 214 and underneath the
channel 127 formed therebetween.
In accordance with certain aspects, the second opening 132 directs the formulation
into the channel in a direction that is substantially orthogonal to the lengthwise
direction of the channel 127. Such exemplary embodiment can be seen, for instance,
with reference to FIGS. 8 and 8A. While the dimensions and/or geometric shape of
the second opening 132 can be adjusted to fit a specific drug delivery application, the
opening 132 is substantially rectangular in shape.
In accordance with yet another illustrative aspect, the bent path 128 comprises a
substantially semi-circular portion that is connected to the conduit for receiving the
formulation from the fluid delivery device 104 and the channel 127. In accordance
with this illustrative aspect, the bent path 128 terminates at the second opening 132,
which in turn, is positioned substantially orthogonally relative to the substantially
semi-circular portion of the bent path 128.
Once the formulation completely travels and circumnavigates the channel 127 and
reaches the distal end 112a of the one or more outlets 112, it is now ready to be
dispensed onto the surface or coat of the animal. As explained above, to spread the
formulation evenly over a surface area of the animal, the outlet 112 can penetrate the
animal's fur and thereby reach the animal's skin. To accomplish this, the outlet 112
may include one or more prongs 129 for assisting with the dispensing of the
formulation onto the surface of the animal. In accordance with certain embodiments,
the prongs 129 comprise spaced feet or tines that are configured to penetrate the fur of
the animal 102 so that the applicator 106 can substantially reach or touch the surface
of the animal's body during the dispensing of the formulation. This penetration
allows a more efficient topical and transdermal release of the agent. In addition, those
of skill in the drug delivery and fluid dispensing arts will understand and appreciate
that the addition of prongs or other such structural projections from the outlet 112 will
discourage capillary action or attraction (i.e., will stop the formulation from moving
upwardly along the outside of the outlet) from happening during the dispensing
action. The minimization and/or elimination of such capillary action effects are
particularly beneficial when dealing with formulations that can be considered harmful
and/or dangerous.
Described herein is a single dose transdermal formulation comprising a
therapeutically effective amount of a composition comprising fentanyl, a penetration
enhancer selected from the group consisting of long chain alkyl para-aminobenzoate,
long chain alkyl dimethyl-para-aminobenzoate, long chain alkyl cinnamate, long
chain alkyl methoxycinnamate, long chain alkyl salicylate, octyl dimethyl-para-
aminobenzoate, octyl para-methoxycinnamate, octyl salicylate, or mixtures thereof,
and a volatile liquid selected from the group consisting of ethanol, ethyl acetate,
isopropanol, acetone, ethyl formate, methanol, methyl acetate, methyl ethyl ketone,
pentane, chloroform, or mixtures thereof suitable for administration. In one
embodiment, the penetration enhancer is octyl salicylate. In one embodiment, the
volatile liquid is isopropanol. In some embodiments, the composition comprises
fentanyl at a dose of about 2.7 mg per kg of canine body weight. In some
embodiments, the single dose transdermal formulation controls pain in the canine for
an effective period of time. In some embodiments, an effective period of time
comprises a period of at least 24 hours, a period of at least 48 hours, a period of at
least 72 hours, a period of at least 96 hours, or a period of at least 7 days. In one
embodiment, the single dose transdermal formulation is administered once every at
least 48 hours. In another embodiment, the single dose transdermal formulation is
administered once every at least 72 hours. In yet another embodiment, the single dose
transdermal formulation is administered once every at least 96 hours. In yet another
embodiment, the single dose transdermal formulation is administered once every at
least 7 days.
According to the methods of the present invention, the term “single dose transdermal
formulation” includes embodiments wherein the composition can be transdermally
administered as a single application and as multiple applications. In one embodiment,
a single dose transdermal formulation of the composition can be transdermally
administered to a canine in a single application at one location on the canine’s skin.
In another embodiment, a single dose transdermal formulation of the composition can
be transdermally administered to a canine in multiple applications at more than one
location on the canine’s skin. In one embodiment, a single dose transdermal
formulation of the composition is transdermally administered to a canine in a single
application at one location on the canine’s skin, wherein the single application is up to
about 0.5 mL of a solution of the composition. In one embodiment, a single dose
transdermal formulation of the composition can be transdermally administered to a
canine in multiple applications at a single location on the canine’s skin. In another
embodiment, a single dose transdermal formulation of the composition is
transdermally administered to a canine in multiple applications at a single location on
the canine’s skin, wherein each application has up to about 0.5 mL of a solution of the
composition. In another embodiment, a single dose transdermal formulation of the
composition is transdermally administered to a canine in multiple applications at more
than one location on the canine’s skin, wherein each application is up to about 0.5 mL
of a solution of the composition. In embodiments wherein multiple applications of
the composition are utilized, the multiple applications can be administered to the
canine over a reasonable duration of time.
The following embodiments are also contemplated:
1. A method of controlling pain comprising transdermally administering to a canine
in need thereof a therapeutically effective amount of a composition comprising
fentanyl, a penetration enhancer, and a volatile liquid,
wherein the composition is a solution.
2. The method of clause 1 wherein the transdermal administration is applied to a
dorsal location of the canine.
3. The method of clause 1 wherein the transdermal administration is applied to a
ventral location of the canine.
4. A method of controlling pain comprising transdermally administering to a canine
in need thereof a therapeutically effective amount of a composition comprising
fentanyl, a penetration enhancer, and a volatile liquid,
wherein the composition is in a solution, and
wherein the transdermal administration is applied to a dorsal location of
the canine.
5. The method of any one of clauses 1 to 4 wherein the composition is administered
as a single dose.
6. The method of any one of clauses 1 to 5 wherein the pain is controlled for an
effective period of time.
7. The method of clause 6 wherein the effective period of time is about 96 hours.
8. A method of treating pain comprising transdermally administering to a canine in
need of treatment a therapeutically effective amount of a composition comprising
fentanyl, a penetration enhancer, and a volatile liquid,
wherein the composition is administered as a single dose, and
wherein the single dose is effective for the treatment of pain for about 96
hours.
9. The method of clause 8 wherein the transdermal administration is applied to a
dorsal location of the canine.
. The method of clause 8 wherein the transdermal administration is applied to a
ventral location of the canine.
11. The method of any one of clauses 1 to 10 wherein the penetration enhancer is
octyl salicylate.
12. The method of any one of clauses 1 to 11 wherein the volatile liquid is
isopropanol.
13. The method of any one of clauses 1 to 12 wherein the pain is associated with a
surgery performed or to be performed on the canine.
14. The method of clause 13 wherein the surgery is an orthopedic surgery.
. The method of clause 13 wherein the surgery is a soft tissue surgery.
16. The method of any one of clauses 13 to 15 wherein the composition is
administered to the canine about 2 to about 4 hours prior to the surgery.
17. The method of clause 16 wherein the composition is administered as a single dose.
18. The method of any one of clauses 1 to 17 wherein the composition is administered
as a single unit dose.
19. The method of any one of clauses 1 to 18 wherein the composition comprises
about 0.1 to about 10% (w/v) of fentanyl, about 0.1 to about 10% (w/v) of the
penetration enhancer, and about 80 to about 99.8% (w/v) of the volatile liquid.
20. The method of any one of clauses 1 to 19 wherein the composition comprises
about 3 to about 7% (w/v) of fentanyl, about 3 to about 7% (w/v) of the penetration
enhancer, and about 86 to about 94% (w/v) of the volatile liquid.
21. The method of any one of clauses 1 to 20 wherein the composition comprises
about 5% (w/v) of fentanyl, about 5% (w/v) of the penetration enhancer, and about
90% (w/v) of the volatile liquid.
22. The method of clause 21 wherein the penetration enhancer is octyl salicylate and
the volatile liquid is isopropanol.
23. The method of any one of clauses 1 to 22 wherein the fentanyl is at a dose of
about 0.1 to about 10 mg/kg of weight of the canine.
24. The method of any one of clauses 1 to 23 wherein the fentanyl is at a dose of
about 1 to about 5 mg/kg of weight of the canine.
. The method of any one of clauses 1 to 24 wherein the fentanyl is at a dose of
about 2.7 mg/kg of weight of the canine.
26. The method of any one of clauses 1 to 25 wherein the composition is administered
with one or more other therapeutic ingredients.
27. The method of any one of clauses 1 to 26 wherein the composition is administered
using a transdermal dispensing apparatus.
28. A single dose transdermal formulation comprising a therapeutically effective
amount of a composition in solution, wherein the composition comprises
fentanyl,
a penetration enhancer selected from the group consisting of long chain
alkyl para-aminobenzoate, long chain alkyl dimethyl-para-aminobenzoate, long chain
alkyl cinnamate, long chain alkyl methoxycinnamate, long chain alkyl salicylate,
octyl dimethyl-para-aminobenzoate, octyl para-methoxycinnamate, octyl salicylate, or
mixtures thereof, and
a volatile liquid selected from the group consisting of ethanol, ethyl
acetate, isopropanol, acetone, ethyl formate, methanol, methyl acetate, methyl ethyl
ketone, pentane, chloroform, or mixtures thereof.
29. The formulation of clause 28 suitable for administration at a dose of about 0.1 to
about 10 mg of fentanyl per kg of canine body weight.
. The formulation of any one of clauses 28 or 29 suitable for administration at a
dose of about 1 to about 5 mg of fentanyl per kg of canine body weight.
31. The formulation of any one of clauses 28 to 30 suitable for administration at a
dose of about 2.7 mg of fentanyl per kg of canine body weight.
32. The formulation of any one of clauses 28 to 31 which is administered once every
at least 72 hours.
33. The formulation of any one of clauses 28 to 31 which is administered once every
at least 96 hours.
In each of the following examples, the composition of the present invention is
administered to canines as a solution formulation. The embodiment of the
composition of the present invention utilized in each example comprised fentanyl at a
concentration of 5% weight/volume (50 mg/mL), octyl salicylate at a concentration of
% weight/volume (50 mg/mL), and isopropanol.
EXAMPLE 1
Pharmacokinetics of a Fentanyl Composition Administered as a Single
Transdermal Dose at a Ventral Location of Canines
The pharmacokinetics of the composition of the present invention (comprising
fentanyl, a penetration enhancer, and a volatile liquid, wherein the composition is a
solution) can be examined following a single transdermal administration at a ventral
location of canines. Eighteen adult beagle canines can be divided into three groups of
six canines (three males and 3 females). Each group can be administered a single
dose of the composition of the present invention comprising a fentanyl concentration
of 1.3 (25), 2.6 (50) or 5.2 mg/kg (100 µL/kg). The dose can be transdermally applied
as a single dose to clipped, ventral abdominal skin from approximately the umbilicus
caudally using a 1-mL tuberculin syringe. Immediately following dosing, collars can
be placed on each canine through 72 hours to prevent direct licking of the application
site. Serial jugular venous blood samples can be collected at 0 (pre-dosing), 1, 2, 4, 6,
8, 12, 24, 36, 48, 60, 72, 84, 96, 108, 120, 144, 168, 240, 336, 408 and 504 hours after
dosing and assayed for fentanyl by LC/MS/MS.
Following administration of a single transdermal dose, fentanyl is absorbed from the
ventral abdominal application site within hours of application through 21 days in a
dose-dependent manner (see Table 2). Fentanyl is rapidly detected with a mean
absorption lag time (t ) of 0.333 hours in the 1.3 mg/kg group and 0 in the other two
treatment groups. The mean maximum observed plasma concentration (C )
increased with increasing doses of fentanyl and were calculated at 2.28, 2.67 and 4.71
ng/mL in the 1.3, 2.6 and 5.2 mg/kg dose groups, respectively. The mean time that
C was achieved (t ) in all groups ranged from approximately 50 to 60 hours.
max max
Table 2. Plasma fentanyl concentrations following application of 1.3, 2.6 or 5.2
mg/kg of the composition of the present invention as a single dose to the ventral
abdomen to canines
Fentanyl Dose mg/kg (µL/kg)
1.3 (25) 2.6 (50) 5.2 (100)
Time Mean Mean Mean
SD SD SD
(hr) (ng/mL) (ng/mL) (ng/mL)
0 0.000 0.000 0.000 0.000 0.000 0.000
1 0.037 0.031 0.083 0.028 0.167 0.107
2 0.108 0.062 0.221 0.058 0.513 0.220
4 0.199 0.100 0.364 0.077 0.876 0.509
6 0.359 0.271 0.592 0.127 1.173 0.536
8 0.492 0.305 0.864 0.201 1.875 0.802
12 0.699 0.376 1.192 0.321 2.851 1.214
24 0.796 0.346 1.383 0.272 3.387 1.141
36 1.598 0.549 2.069 0.631 3.692 0.828
48 1.733 0.877 2.244 1.361 3.230 0.690
60 1.864 1.016 2.013 1.093 3.608 1.019
72 1.314 0.582 1.613 0.653 3.246 0.773
84 0.724 0.456 1.194 0.592 3.985 2.078
96 0.761 0.364 1.131 0.455 3.288 1.091
108 0.744 0.759 1.336 0.727 2.886 0.749
120 0.565 0.233 1.268 0.264 2.594 0.708
144 0.286 0.162 0.663 0.376 1.592 0.162
168 0.267 0.115 0.615 0.343 1.597 0.415
240 0.085 0.045 0.274 0.208 0.914 0.426
336 0.020 0.033 0.085 0.064 0.377 0.229
408 0.006 0.015 0.070 0.069 0.198 0.138
504 0.005 0.012 0.020 0.023 0.185 0.140
Mean elimination half-lives were 53.7, 69.6 and 103 hours in the 1.3, 2.6 and 5.2
mg/kg dose groups, respectively. These observations are in marked contrast to the
fentanyl half-life following an intravenous injection of fentanyl citrate, where the
half-life ranges from 0.76 to 6.0 hours.
Plasma fentanyl concentrations less than the lower limit of quantification (LLOQ,
0.025 ng/mL) were set equal to zero ng/mL for descriptive statistic calculations. The
mean area under the plasma concentration-time curve calculation from time 0 to the
time of the last sample at or above the lower limit of quantification LLOQ (AUC
) from lowest to highest dose groups were 157, 269 and 645 ng·hour/mL, and
LLOQ
were dose proportional where R was 0.9818.
A presumed minimum effective plasma concentration (MEC) of 0.2 to 1.2 ng/mL was
used in the present example. Mean plasma fentanyl concentrations for the 1.3 mg/kg
dose group remained at or above the lower and higher end of the MEC range from 4
to 168 hours and 36 to 72 hours, respectively. In contrast, at the 2.6 mg/kg dose, the
mean plasma fentanyl concentrations remained ≥ 0.2 ng/mL from 2 to 240 hours and
≥1.2 ng/mL from 12 to approximately 84-120 hours. With the higher dose of 5.2
mg/kg, mean concentrations remained ≥ 0.2 ng/mL from 1 to 504 hours and ≥ 1.2
ng/mL from 6 to 168 hours. Therefore, the onset of a 1.3 mg/kg dose in a canine
could be from 4 to 36 hours with a duration of 3 to 7 days. For a dose of 2.6 mg/kg,
the onset could be from 2 to 12 hours with a duration of 3.5 to 10 days. Finally, for a
dose of 5.2 mg/kg, the onset could be from 1 to 8 hours with a duration of 7 to 17
days.
To establish a dose, both safety and effectiveness must be considered. In human
beings, a dose limiting effect is opioid-induced hypercapnia and respiratory
depression. Such a profound response in humans has resulted in contraindication of a
fentanyl patch for post-operative pain. In contrast, this is not a problem in canines in
that spontaneous respirations are maintained independent of fentanyl concentration.
Plasma fentanyl concentrations as high as approximately 80 ng/mL are not fatal and
reduce the respiratory rate by only approximately 11 breaths/minute (50%) in
spontaneously breathing canines. Additionally, the respiratory rate, oxygen
consumption and blood gases (pCO , pO , and pH) do not change further as
concentrations increase above 100 ng/ml.
The mean C from the lowest to the highest dose in the present study were 2.28,
2.67 and 4.71 ng/mL and is well below concentrations that have a clinical impact on
respiratory rates in canines. The primary dose limiting effect appeared to be
decreased appetite and sedation in the 5.2 mg/kg dose group. One canine in this dose
group required parenteral fluid therapy and forced feeding from 72 to 96 hours due to
lack of food and water intake and 4 canines were sedated for 3 days. The 2.6 mg/kg
group did not have any adverse events and had a faster presumed onset of action and
longer duration than the 1.3 mg/kg group.
In summary, the 2.6 mg/kg (50 µL/kg) fentanyl dose group demonstrated a more rapid
onset of action and longer duration of action compared to the 1.3 mg/kg fentanyl dose
group following administration to a ventral location of canines. Furthermore, the 2.6
mg/kg fentanyl dose group demonstrated fewer observed adverse events compared to
the 5.2 mg/kg fentanyl dose group.
EXAMPLE 2
Pharmacokinetics of a Fentanyl Composition Administered as a Single
Transdermal Dose at a Ventral Location Compared to a Dorsal Location of
Canines
The pharmacokinetics of the composition of the present invention can be examined
following a single transdermal administration of the composition to different
anatomical sites on a canine. Generally, application of transdermal drugs to different
anatomical sites can result in different absorption characteristics. There may be
advantages of applying the composition of the present invention to sites other than the
ventral abdomen. For example, dorsal inter-scapular application allows ambulatory
canines to be walked to and from a treatment area for ease of application and is far
from a laparotomy surgical site. However, different transdermal application sites are
known to result in dissimilar drug delivery characteristics. The abdomen versus back
skin in canines has been shown to differ with regard to blood flow and therefore
different absorption characteristics may be apparent when drugs are applied to these
sites. Therefore, the pharmacokinetics of the composition of the present invention
may differ when the composition is applied topically to the ventral abdominal versus
the dorsal inter-scapular areas of canines.
Forty purpose-bred laboratory beagle canines (Marshall BioResources, North Rose,
NY) were selected for the present study (20 males and 20 females, all 6 to 8 months
of age at the time of dosing). Canines were administered 2.6 mg/kg (50 µL/kg) of the
composition of the present invention applied as a single dose to the dorsal
interscalpular region or ventral abdominal skin near the umbilicus. Canines were
randomly allotted to dorsal or ventral dosing in parallel study design.
The mean plasma fentanyl concentrations by application site are displayed in Table 3.
Plasma fentanyl concentrations rose more rapidly following dorsal application and
persisted longer in the ventral application group. Mean plasma fentanyl
concentrations remained above 0.6 ng/mL from 4-96 hours in the dorsal application
group and 8-144 hours in the ventral application group.
Table 3. Plasma fentanyl concentrations by treatment group (n = 20/group)
following administration of the composition of the present invention
Ventral Application Dorsal Application
Standar Standar
Time Mean Mean
Deviati C.V. Deviati C.V.
(hou (ng/m (ng/m
on (%) on (%)
r) L) L)
(ng/mL (ng/mL
0 0.000 0.000 NA 0.000 0.000 NA
158.1 83.1
0.189 0.298 % 0.319 0.265 %
90.3 111.7
0.425 0.384 % 0.920 1.028 %
36.9 18.3
0.796 0.294 % 1.18 0.215 %
43.5 23.7
1.28 0.557 % 1.65 0.391 %
43.3 26.8
1.79 0.775 % 1.50 0.401 %
49.1 33.3
1.48 0.728 % 1.36 0.453 %
73.9 35.8
1.59 1.18 % 1.35 0.483 %
50.2 27.6
1.14 0.571 % 0.725 0.200 %
36.6 33.1
0.907 0.332 % 0.61 0.20 %
27.1 34.4
0.755 0.204 % 0.458 0.157 %
85.5 19.2
0.835 0.714 % 0.461 0.0887 %
22.9 25.1
0.536 0.123 % 0.315 0.0790 %
28.5 33.4
0.411 0.117 % 0.278 0.0927 %
49.3 47.6
0.343 0.169 % 0.178 0.0848 %
68.7 91.4
0.206 0.142 % 0.0842 0.0770 %
102.6 154.5
0.129 0.133 % 0.0418 0.0646 %
120.6
0.074 0.090 % 0.000 0.000 NA
NA: Not applicable
The pharmacokinetic parameters by application site group are summarized in Table 4.
The C was 2.34 ± 1.29 (mean ± standard deviation) and 2.02 ± 0.84 ng/mL for the
ventral and dorsal application groups, respectively. The t was 40.2 ± 29.5 and 24.8
± 17.8 hours in the ventral and dorsal application site groups, respectively. The
terminal elimination half-lives (t ) for both groups were similar with values of 137 ±
58.9 and 117 ± 56.6 hours for the ventral and dorsal application site groups,
respectively. Less than 20% of the AUC was extrapolated for both groups,
indicating that AUC sufficiently reflects the extent of exposure.
0-LLOQ
Table 4. Pharmacokinetic parameters by treatment group (n = 20/group)
following administration of the composition of the present invention.
Ventral Application Dorsal Application
Standard Standard
Parameter Mean Mean
deviation deviation
2.34 1.29 2.02 0.840
(ng/mL)
40.2 29.5 24.8 17.8
(hour)
0-LLOQ
251 75.1 170 29.0
(ng·hour/mL)
282 82.5 198 33.9
(ng·hour/mL)
11.6 5.06 13.4 7.40
Extrapolated
137 58.9 117 59.6
(hour)
The bioequivalence analysis results are displayed in Table 5. The dorsal to ventral
ratio of the geometric means for AUC was 70.5% (90% CI [60.6-82.0%]) and
0-LLOQ
for C ratio of the geometric means was 93.1% (90% CI [73.4-118%]).
Table 5. Ratio (dorsal:ventral) of the geometric means and 90% confidence
interval of selected pharmacokinetic parameters (n = 20/group).
Lower 90% Ration of the Upper 90%
Parameter Confidence Geometric Confidence
Interval Means Interval
AUC 60.6% 70.5% 82.0%
0-LLOQ
C 73.4% 93.1% 118%
There were no adverse events in this study. A single canine in the dorsal application
group had a plasma fentanyl concentration of 13.0 ng/mL at 96 hours compared to the
group mean of 0.61 ng/mL. Moderate to severe sedation would be expected at
concentrations near or above 15 ng/mL. No sedation or adverse events were noted at
the time of the observed elevated concentration at 96 hours and the 72 and 120 hour
plasma fentanyl concentrations in this subject were below 1.0 ng/mL. Therefore, the
transient spike was considered spurious and was dropped from further
pharmacokinetic analysis.
The absorption of the composition of the present invention in canines is not
equivalent when applied to the dorsal inter-scapular area versus the ventral abdominal
area. Absorption was more rapid for dorsally applied composition of the present
invention, supporting a more rapid onset of action compared to ventral application.
Whereas the mean time to achieve a concentration of 0.6 ng/mL was 4 hours for
dorsal application, ventral application did reach this concentration until 8 hours
following dosing. The more rapid absorption associated with dorsal application was
also associated with a difference in mean duration above 0.6 ng/mL. The mean time
to drop below 0.6 ng/mL for dorsal and ventral application was 96 and 144 hours,
respectively (see Table 3).
Dorsal administration achieved an absorption rate of ≥ 2 µg/kg/hour from 2 to 144
hours following application with a peak of 9.8 µg/kg/hour occurring at 12 hours. In
contrast, ventral administration achieved an absorption rate of ≥ 2 µg/kg/hour from 2
to 264 hours with a peak of 8.5 µg/kg/hour occurring at 24 hours. These results
suggest that potentially analgesic infusion rates from the composition of the present
invention are achieved within a few hours of application and are maintained for
periods of up to 10 days.
In summary, both dorsal and ventral application sites resulted in absorption rates of
greater than 2 µg/kg/hour within 2 hours of transdermal application to canines, but the
dorsal site achieved mean plasma concentration of 0.6 ng/mL by 4 hours compared to
8 hours with ventral application. Therefore, dorsal application provides a more rapid
onset of action. With such a rapid onset of action, the composition of the present
invention could be applied to a canine as it enters the hospital as an anesthetic
premedication with analgesic concentrations potentially occurring 2-4 hours prior to
surgery. Without additional opioid administration, this single dose could have a
duration of a minimum of 96 hours.
EXAMPLE 3
Pharmacokinetics of a Fentanyl Composition Administered as a Single
Transdermal Dose at a Dorsal Location of Canines
The pharmacokinetics of the composition of the present invention (comprising
fentanyl, a penetration enhancer, and a volatile liquid, wherein the composition is a
solution) can be examined following a single transdermal administration at a dorsal
location of canines. Twenty purpose-bred laboratory beagle canines (10 males and 10
females) can be administered a single dose of the composition of the present invention
(comprising 2.6 mg/kg of fentanyl) to the dorsal, interscapular region. Blood samples
for plasma fentanyl analysis by LC-MS/MS can be collected from pre-dose
administration through 21 days post-dose administration (i.e., collection at 0, 2, 4, 8,
12, 24, 36, 48, 72, 96, 120, 144, 168, 216, 264, 336, 408 and 504 hours after dosing).
Pharmacokinetics can be determined using noncompartmental pharmacokinetic
analysis methods.
Following administration of the composition of the present invention, the mean
plasma fentanyl concentrations rose rapidly with all canines demonstrating
measureable plasma fentanyl concentrations (> 0.100 ng/mL) by 2 hours after dose
administration (see Table 6). The mean plasma fentanyl concentrations reached the
maximum value around 12 hours post-dose administration, and gradually declined
thereafter until all samples were less than 0.100 ng/mL at 504 hours. The mean
plasma fentanyl concentrations remained above 0.5 ng/mL from 4 through 96 hours
post-dose administration.
Table 6. Mean concentration of fentanyl in canines (n = 20) following
administration of the composition of the present invention.
Standard
Time Mean C.V.
Deviation
(hour) (ng/mL) (%)
(ng/mL)
0 0.00 0.00 NA
2 0.319 0.265 83.1%
4 0.920 1.03 112%
8 1.18 0.215 18.2%
12 1.65 0.391 23.7%
24 1.50 0.401 26.7%
36 1.36 0.453 33.3%
48 1.35 0.483 35.8%
72 0.725 0.200 27.6%
96 1.23 2.78 226%
120 0.458 0.157 34.3%
144 0.461 0.0887 19.2%
168 0.315 0.0790 25.1%
216 0.278 0.0927 33.3%
264 0.178 0.0848 47.6%
336 0.0842 0.0770 91.4%
408 0.0418 0.0646 155%
504 0.00 0.00 NA
NA: Not applicable
The coefficient of variation (C.V.) of the plasma fentanyl samples was generally
around 50%. A relatively high C.V. was observed at 96 hours due to single canine
having a transiently high plasma fentanyl concentration of 13.0 ng/mL at 96 hours.
The plasma fentanyl concentrations at the adjacent 72 and 120 hour samples for this
subject were both below 1.0 ng/mL. No sedation or other side-effects were observed
at 96 hours, even though sedation would be expected in a canine with a plasma
fentanyl concentration of 13.0 ng/mL. The cause of the transient increase in the
plasma fentanyl concentration is unknown.
The results from the noncompartmental pharmacokinetic analysis are displayed in
Table 7. The mean C was 2.58 ng/mL (2.59 standard deviation). However, the
results were highly influenced by the single transiently high plasma fentanyl
concentration of 13.0 ng/mL at 96 hours. Exclusion of this single sample from the
mean and standard deviation calculation results in C values of 2.02 and 0.840
ng/mL, respectively.
Table 7. Parameters from noncompartmental pharmacokinetic analysis (n = 20).
Parameter Mean Standard deviation
2.58 2.59
(ng/mL)
29.0 23.6
(hour)
0-LLOQ
181 59.7
(ng·hour/mL)
206 64.4
(ng·hour/mL)
AUC Extrapolated
11.8 7.48
117 61.5
(hour)
† Removal of single subject’s 96 hour sample of 13.0 ng/mL results in a C mean
and standard deviation of 2.02 and 0.840 ng/mL, respectively.
The t was 29.0 (23.6) hours and the t was 117 (61.5) hours. The percent
max ½
extrapolated AUC was only 11.8 (7.48) %, indicating a sufficient portion of the
plasma concentration-time profile was observed to accurately quantify the AUC
and t . The AUC was 206 (64.4) ng·hour/mL, corresponding to a large
½ 0-∞
bioavailability normalized clearance (i.e. ) of 13.5 (3.44) L/hr·kg. The exclusion
of the single sample with a transiently high plasma concentration at 96 hours had
minimal impact on the pharmacokinetic parameters other than C and therefore
results excluding this plasma sample are not presented for the other parameters.
Compared to the fentanyl transdermal patch use in canines at dose rates of 50 to 100
µg/h, the mean plasma fentanyl concentrations reached 0.6 ng/mL more rapidly
following a 2.6 mg/kg dose of the composition of the present invention. Following
administration of the composition, the mean plasma fentanyl concentrations reached
0.6 ng/mL within 4 hours of dose administration (see Table 6) compared to 10 to 30
hours with transdermal patch application. Thus, analgesic concentrations will be
more rapidly reached following application of the composition of the present
invention compared to transdermal fentanyl patches, reducing the time pre-surgery
that the fentanyl must be administered. Additionally, the mean plasma fentanyl
concentrations remained above 0.6 ng/mL for 92 hours following administration of
the composition of the present invention, while they only remained above this
concentration for 18 to 62 hours with the transdermal patch. The administration of 50
µg/h transdermal fentanyl patch in 6 male beagle canines resulted in relatively
constant plasma fentanyl concentrations from 24 to 72 hours post-application with a
mean concentration of approximately 1.6 ng/mL. In comparison, the mean plasma
fentanyl concentration of the composition of the present invention gradually fell from
1.50 ng/mL at 24 hours to 0.725 ng/mL at 72 hours, with a mean concentration of
1.23 ng/mL (see Table 6).
The pharmacokinetic parameter results for the composition of the present invention
(see Table 7) were similar to a recent study of the fentanyl transdermal patch where
the mean C and t values were 2.1 ng/mL and 22 hours, respectively. In that
max max
study, the size of the patch applied depended on the canine bodyweight, with an
approximate targeted dose of approximately 3 µg/hr/kg of bodyweight.
No adverse side-effects or application site skin reactions were observed during the
study.
In summary, methods of the present invention administered at a dorsal location of
canines can overcome the main limitations of orally or parenterally administered
fentanyl and, in addition, many of the limitations of the fentanyl transdermal patch.
EXAMPLE 4
Population Pharmacokinetics of a Fentanyl Composition Administered as a
Single Transdermal Dose Administered to Canines Prior to Soft Tissue or
Orthopedic Surgery
A study of the methods of the present invention can be undertaken to determine
transdermal administration of the composition of the present invention in canines
undergoing surgical procedures. Enrolled canines can be randomized to receive either
the composition of the present invention or the positive control subcutaneous
oxymorphone (Opana® Injection, Endo Pharmaceuticals Inc., Chadds Ford,
Pennsylvania). Canines randomized to receive the composition of the present
invention treatment group can be administered a single 2.7 mg/kg (54 µL/kg) fentanyl
dose to the dorsal scapular area two to four hours prior to either orthopedic or soft-
tissue surgery. Canines randomized to the positive control treatment group can be
administered oxymorphone subcutaneously 2-4 hours prior to surgery, at the time of
extubation, and every 6 hours through 90 hours post-extubation. Oxymorphone HCl
can be administered at the FDA approved dose in canines of approximately 0.1-0.2
mg/kg.
Plasma fentanyl concentrations can be determined from 215 canines following
administration of a single dose of the composition of the present invention. A
population pharmacokinetic model was fit to the resulting data, with a 1-compartment
open pharmacokinetic model with first-order absorption and an absorption lag-time
best fitting the data. No tested clinical covariates had a significant effect on the
pharmacokinetics of the composition of the present invention. The final model
adequately described the population pharmacokinetics and gave results consistent
with laboratory pharmacokinetic studies in healthy canines.
Using the final model population median parameter estimates (see Table 8), the
estimated area under the fentanyl plasma concentration-time curve from time 0 to
infinity (AUC ) was 220 ng•hr/mL for a “typical” subject. Additionally, the
estimated average concentration from 0 to 4 days (96 hours) for a typical clinical
patient was 1.32 ng/mL, which is likely to be analgesic in canines. The estimated
maximum plasma concentration (C ) and time of C occurrence (t ) was 1.83
max max max
ng/mL and 13.6 hours for a typical subject, respectively. Finally, the estimated
terminal half-life (t½) was 74.0 hr for a typical subject. The long t½ is consistent with
the previously recognized flip-flop pharmacokinetics of the composition of the
present invention since intravenously administered fentanyl has a t½ of approximately
0.76 to 6.0 hours.
Table 8. Population pharmacokinetic model parameter estimates (n = 215
subjects). Values represented as the estimate (standard error).
Parameter Median
Variance ( )
t 0.552 0.0517
(hr) (1.63) (12.3)
k 0.267 0.0581
(1/hr) (0.167) (0.745)
1.26 0.346
(0.130) (0.0694)
(10 L/kg)
k 0.00937 0.00204
(1/hr) (0.00165) (0.140)
0.301
b* NA
(0.0765)
*Scaler of the proportional residual error model; NA: Not applicable
The plasma fentanyl concentrations were sustained over days in the range considered
to be analgesic for postoperative pain in canines. The time to reach 0.5 ng/mL in a
typical canine patient administered the composition of the present invention was 1.60
hours, compared to 10 to 30 hours with fentanyl transdermal patch application in
canines. The administration of 50 µg/h fentanyl transdermal patch in 6 male beagle
canines resulted in mean plasma fentanyl concentrations of approximately 1.6 ng/mL
from 24 to 72 hours post-application. In comparison, the observed mean
concentration of plasma fentanyl with the composition in the present study was 1.82
ng/mL from 24 to 72 hours post-application.
In summary, following dorsal administration to canines, a 1-compartment open
pharmacokinetic model with first order absorption and an absorption lag-time best
described the pharmacokinetics of a single application of the composition of the
present invention at a dose of 2.7 mg/kg of fentanyl in the target clinical population.
For canines administered the composition of the present invention, both the observed
and predicted plasma fentanyl concentrations were sustained over days in the range
considered to be analgesic for postoperative pain in canines.
EXAMPLE 5
Comparison of a Transdermal Fentanyl Composition and Oxymorphone for the
Control of Post-Operative Pain in Canines
The safety and effectiveness of the composition of the present invention compared to
oxymorphone hydrochloride can be examined for the control of post-operative pain
over a period of four days. Canines can be randomly assigned to a single transdermal
dose of the composition of the present invention (2.7 mg/kg [1.2 mg/lb]) applied 2-4
hours prior to surgery or oxymorphone hydrochloride (0.1-0.2 mg/kg [0.22-0.44
mg/lb]) administered subcutaneously 2-4 hours prior to surgery and then administered
every 6 hours subsequently through 90 hours post-surgery. Canines randomized to
receive the composition of the present invention can be administered a single dose of
2.7 mg/kg (1.2 mg/lb [approximately 50 µL/kg]) to the dorsal scapular area 2-4 hours
prior to surgery. Pain can be evaluated by blinded observers using the Glasgow
modified pain scale and the a priori criteria for treatment failure was a pain score ≥ 8
(20 maximum score) or adverse events necessitating withdrawal.
In the present example, 502 canines of various breeds were enrolled and were
approximately equally divided between the composition of the present invention
(N=249) and oxymorphone (N=253). Canines were divided between soft tissue
(N=250) and orthopedic surgical procedures (N=251). Four canines treated with the
composition of the present invention were withdrawn due to lack of pain control (pain
score ≥ 8) and 1 due to death unrelated to fentanyl. Eight oxymorphone-treated
canines were withdrawn due to lack of pain control, 18 due to severe adverse events
and 1 due to death unrelated to oxymorphone.
The primary variable for determining effectiveness was a non-inferiority evaluation of
the treatment failure rate of the composition of the present invention (i.e., a
composition comprising fentanyl) and oxymorphone. The upper bound for the margin
of difference between fentanyl-oxymorphone treatment failure rates was to be no
greater than 15% for fentanyl to be considered non-inferior to oxymorphone. The
dropout rate for fentanyl was 2.01% and the dropout rate for oxymorphone was
.76% with a mean difference of -8.7% (see Table 9). The one-sided upper 95%
confidence bound was –6.2%, which was not greater than the a priori selected margin
difference of 15%. Therefore, based on treatment failure rate, administration of the
composition of the present invention (i.e., a composition comprising fentanyl) was
non-inferior to oxymorphone.
Table 9. Non-inferiority analysis of treatment failures.
Transdermal Oxymorphone Difference
Fentanyl Solution (N=251)
(N=249)
Treatment Failures Treatment Failures Mean SE Upper
n % n %
4 2.01 27 10.76 -8.7 1.5 -6.2
*The transdermal fentanyl solution dropout rate was non-inferior to the oxymorphone
dropout rate as the upper 95% CI of the percent difference was contained within the
15% a priori margin of difference.
A secondary non-inferiority analysis compared fentanyl to oxymorphone with respect
to the pain intensity scores at each pain assessment period. Pain scores were highest 2
hours following extubation in both groups where mean values were 2.32 in fentanyl-
and 2.64 in oxymorphone-treated canines. Pain scores declined over the 4 day study
duration such that by Day 4, mean pain scores ranged from 0.830 in fentanyl- and
1.28 in oxymorphone-treated canines. At all time points with the exception of the 1
hour pain assessment, the composition of the present invention was non-inferior to
oxymorphone.
An additional secondary non-inferiority analysis compared fentanyl to oxymorphone
with respect to SPID (see Table 10). The mean sum of pain intensity scores was
18.636 for fentanyl- and 21.662 for oxymorphone-treated canines, respectively. The
upper bound for the SPID between fentanyl-oxymorphone was to be no greater than
26% for fentanyl to be considered non-inferior to oxymorphone. The upper bound for
the SPID between fentanyl - oxymorphone was 0.432, which was not greater than
26%. Therefore, based on SPID, the composition of the present invention was non-
inferior to oxymorphone.
Table 10. Sum of pain intensity score summary statistics over the entire post-
surgical period, SPID and the one-sided upper 95% confidence bound for the
difference.
Statistic Transdermal Oxymorphone SPID One-Sided
Fentanyl Upper
Solution 95% CI*
Mean 18.636 21.662 -3.026 0.432
N 118 65
SD 12.563 15.333
SE 1.157 1.902
Median 15 19
Min 0 0
Max 55 72
*The SPID for fentanyl-oxymorphone was non-inferior as the upper 95% CI is
contained within the 26% a priori margin of difference.
Canines with sedation scores ≥2 prior to a scheduled pain assessment were not scored
for pain because excess sedation interfered with the pain assessor’s ability to
adequately evaluate analgesia by use of the modified Glasgow composite pain scale.
At no time was the mean sedation score ≥2 in either treatment group. Sedation scores
were highest at the first pain assessment time, 1 hour post-extubation where the mean
sedation scores were 1.67 and 1.98 in the fentanyl- and oxymorphone-treated canines,
respectively. By 6 hours post-extubation, mean sedation scores in both groups were
less than 1 (mild); 0.81 and 0.97 for fentanyl and oxymorphone, respectively. At 1
hour postextubation, 49% of fentanyl-treated canines had a sedation scores ≥2 and by
12 hours this had diminished to 7% of canines. By 24 hours, 3% of fentanyl-treated
canines had a sedation scores ≥2 and none beyond 48 hours. The number of
oxymorphone treated canines with sedation scores ≥2 was greater at each assessment
period compared to fentanyl. At 1 hour post-extubation, 70% of oxymorphone-treated
canines had a sedation scores ≥2 and 11% of canines remained moderated sedated at
12 hours. By 24 hours, 7% of oxymorphone-treated canines had a sedation scores ≥2
and 3% to 0.9% of canines were moderately sedated throughout remaining 4 day
study period.
Overall, adverse events associated with oxymorphone were greater in both number
and severity compared to the composition of the present invention. There were a total
of 56 individual adverse events reported in 44 (17.7%) fentanyl-treated canines; 46
were categorized as mild, 9 moderate and 1 severe (see Table 11). In oxymorphone-
treated canines, there were a total of 228 adverse events reported in 84 (33.7%)
canines; 125 were categorized as mild, 75 moderate and 28 severe. The incidence of
adverse events in fentanyl-treated canines was infrequent over time with a slightly
greater incidence for some adverse events within the first 48 hours of surgery (see
Table 12). Over the first 48 hours, the most frequent adverse events were diarrhea
ranging from 0.4-2%, emesis ranging from 0-1.6%, hypothermia ranging from 1.5-
4.4% and anorexia ranging from 0-0.8%. The incidence of adverse in oxymorphone-
treated canines was higher in some categories compared to fentanyl and persisted
throughout the 4 day study period (see Table 13). Over the 4 day study period, emesis
ranged from 1.6-8.7% and hypothermia ranged from 1.4-9.5%. There were two
deaths in this study; one each in the fentanyl- and oxymorphone- treated groups. In
both instances, the deaths were judged to be unrelated to investigational or control
drug treatment.
Table 11. The number of adverse events in each treatment group by adverse
event severity category.
Number of Adverse Events
Adverse Event Transdermal Oxymorphone
Severity Category Fentanyl Solution (N=253)
(N=249)
Mild 46 125
Moderate 9 75
Severe 1 28
Total 56 228
Table 12. Adverse events by study day in dogs treated with transdermal fentanyl
solution.
Adverse Event Day 0 Day 1 Day 2 Day 3 Day 4
(N=249)
N (%) N (%) N (%) N (%) N (%)
Diarrhea 1 5 2 1 0
(0.4%) (2.0%) (0.8% (0.4% (0.0%
) ) )
Emesis 0 4 2 2 0
(0.0%) (1.6%) (0.8% (0.8% (0.0%
) ) )
Hypothermia 4 11 0 0 0
(1.6%) (4.4%) (0.0% (0.0% (0.0%
) ) )
Pyrexia 0 0 1 1 0
(0.0%) (0.0%) (0.4% (0.4% (0.0%
) ) )
Anorexia 0 2 1 0 0
(0.0%) (0.8%) (0.4% (0.0% (0.0%
) ) )
Constipation 0 0 0 0 0
(0.0%) (0.0%) (0.0% (0.0% (0.0%
) ) )
Hypersalivation 0 0 0 0 0
(0.0%) (0.0%) (0.0% (0.0% (0.0%
) ) )
Conjunctivitis 0 0 0 0 0
(0.0%) (0.0%) (0.0% (0.0% (0.0%
) ) )
Death 0 0 0 1 0
(0.0%) (0.0%) (0.0% (0.4% (0.0%
) ) )
Table 13. Adverse events by study day in dogs treated with oxymorphone.
Adverse Event Day 0 Day 1 Day 2 Day 3 Day 4
(N=252)
N (%) N (%) N (%) N (%) N (%)
Diarrhea 3 3 5 4 0
(1.2%) (1.2%) (2.0% (1.6% (0.0%
) ) )
Emesis 10 11 22 15 4
(4.0%) (4.4%) (8.7% (6.0% (1.6%
) ) )
Hypothermia 16 24 4 5 4
(6.3%) (9.5%) (1.6% (2.0% (1.6%
) ) )
Pyrexia 0 0 0 1 0
(0.0%) (0.0%) (0.0% (0.4% (0.0%
) ) )
Anorexia 0 5 4 2 1
(0.0%) (2.0%) (1.6% (0.8% (0.4%
) ) )
Constipation 0 1 0 0 0
(0.0%) (0.4%) (0.0% (0.0% (0.0%
) ) )
Hypersalivation 5 1 1 0 1
(2.0%) (0.4%) (0.4% (0.0% (0.4%
) ) )
Conjunctivitis 0 1 0 0 0
(0.0%) (0.4%) (0.0% (0.0% (0.0%
) ) )
Death 0 0 1 0 0
(0.0%) (0.0%) (0.4% (0.0% (0.0%
) ) )
In summary, a single dose of the composition of the present invention applied
topically 2-4 hours prior to surgery is safe and effective for the control of pain
associated with orthopedic and soft tissue surgery in canines and provides analgesia
for at least 96 hours. A sustained, steady-state fentanyl delivery provided by a single
preemptive dose of the composition of the present invention provides equianalgesia
compared to repeated injections of oxymorphone over 96 hours with less adverse
events.
EXAMPLE 6
Margin of Safety of a Single Transdermal Dose of a Fentanyl Composition
Administered at Multiples of the Therapeutic Dose to Canines
The margin of safety following application at a multiple dose of the composition of
the present invention can be examined. Twenty-four healthy purpose bred laboratory
mixed-breed hound canines (12 males/12 females) were administered a single placebo
or increasing doses of the composition of the present invention to the ventral
abdominal skin and observed for 14 days. Doses of the composition were
administered at 2.6 (1X), 7.8 (3X), or 13.0 (5X) mg/kg based on canine body weight.
Plasma fentanyl concentrations increased with dose and were detectable (> 0.025
ng/mL) at the first sampling point 30 minutes post-dosing through 14 days in each
group (see Table 14). Mean C were 3.18, 7.27 and 13.5 ng/mL and AUC0-LLOQ
were 323, 824 and 1272 ng•hour/mL in the 1X, 3X and 5X groups, respectively (see
Table 15). Half-lives in all three dose groups were approximately 70 hours.
Exposure to fentanyl, as measured by AUC , was dose proportional.
0-LLOQ
Table 14. Plasma fentanyl concentrations (ng/mL) summary statistics by
treatment group (n = 6/group)
Time 1X (2.6 mg/kg) 3X (7.8 mg/kg) 5X (13.0 mg/kg)
(hr) Mean SD Mean SD Mean SD
0 0 0 0 0 0 0
0.5 0.02 0.02 0.18 0.19 0.17 0.03
1 0.20 0.11 0.57 0.36 1.04 0.36
2 0.51 0.24 1.66 0.79 2.30 0.46
4 1.00 0.36 3.34 1.53 4.48 1.26
8 1.87 0.33 4.38 1.94 8.38 3.48
12 3.00 0.95 6.03 2.34 12.20 5.01
24 2.82 0.92 6.30 0.79 12.68 3.54
36 2.11 0.82 4.72 1.34 11.18 3.81
48 1.80 0.44 5.05 1.63 8.51 3.22
60 2.35 0.79 5.04 1.40 9.19 1.81
72 2.03 0.93 4.45 2.09 7.19 2.21
96 1.47 0.31 3.83 2.22 5.54 2.70
120 0.97 0.29 3.47 2.04 3.75 1.74
144 1.01 0.42 2.63 1.88 3.29 2.13
168 0.60 0.22 1.66 0.62 1.85 0.65
192 0.35 0.18 1.11 0.37 1.19 0.40
216 0.36 0.22 1.06 0.44 1.29 0.57
240 0.27 0.18 1.05 0.33 1.00 0.47
264 0.30 0.23 0.87 0.33 1.04 0.44
288 0.23 0.14 0.71 0.19 0.96 0.45
312 0.10 0.06 0.34 0.13 0.40 0.22
336 0.15 0.10 0.53 0.16 0.58 0.19
SD: Standard deviation.
Table 15. Pharmacokinetic parameters by treatment group (n = 6/group).
1X (2.6 mg/kg) 3X (7.8 mg/kg) 5X (13.0 mg/kg)
Parameter Mean SD Mean SD Mean SD
3.18 0.85 7.27 1.39 13.5 4.12
(ng/mL)
16 6.20 28 21.0 28 22.3
(hour)
0-LLOQ
323 80.5 824 258 1272 315
(ng·hour/mL)
339 88.6 883 255 1333 326
(ng·hour/mL)
4.74 3.10 7.13 3.14 4.63 2.03
Extrapolated
71.2 15.1 75.8 11.2 72.3 15.1
(hour)
SD: Standard deviation
Sedation was not observed in the placebo group. A few incidences of slight sedation
were observed in the 1X group over 24 hours beginning within 4 hours of dosing (see
Table 16). In the 3X and 5X groups, sedation was evident within 1 hour of dosing
through Day 5 and 4, respectively (see Table 16). Moderate to severe sedation was
limited to the 3X and 5X groups, observed from 2.5 hours post-dose administration
until Day 3. Canines in the 3X and 5X groups were supplemented with 40-60
mL/kg/day subcutaneous fluids (Normosol-R, Hospira, Inc., Lake Forest, IL) on Days
0 and 1 because it was determined that they were not consuming maintenance water
quantities due to excess sedation.
Table 16. Mean sedation scores* by dose group (n = 6 per group) vs. time.
Time
Control 1X 3X 5X
Day Hour
0 1 0 0 0.50 1.00
0 2.5 0 0 1.33 2.50
0 4 0 0.33 2.00 2.67
1 1 0 0.33 2.17 2.83
1 2.5 0 0.17 2.00 2.83
1 4 0 0.17 2.00 2.83
2 1 0 0 1.33 2.33
2 2.5 0 0 1.33 2.33
2 4 0 0 1.33 2.33
3 – 0 0 0.33 0.50
4 – 0 0 0.33 0.33
– 0 0 0.33 0
6 – 0 0 0 0
7 – 0 0 0 0
8 – 0 0 0 0
9 – 0 0 0 0
– 0 0 0 0
11 – 0 0 0 0
12 – 0 0 0 0
13 – 0 0 0 0
14 – 0 0 0 0
*0 = no sedation, 1 = slight, 2 = moderate, 3 = severe
Mean food consumption decreased in all treated dose groups following dosing. The
greatest decrease in food consumption was in the 5X group where no food was
consumed on Days 0 through 2. Food consumption had returned to pretreatment
amounts by Day 4 in the 1X group and Day 6 in the 3X and 5X groups. Mean body
weights decreased slightly in the 1X group over 7 days and to a slightly greater extent
in the 3X and 5X groups. Over the 14 day study period there were 4, 1, 4 and 3
vomiting events in the placebo, 1X, 3X and 5X groups, respectively. Over the 14 day
study period there were 1, 6, 21 and 25 abnormal feces occurrences, including dark or
red stools and diarrhea or mucoid feces, in the placebo, 1X, 3X and 5X groups,
respectively. Abnormal feces in the 1X group was limited to Days 1 to 3 whereas in
the 3X and 5X groups, abnormal feces were more sporadic beginning at Day 4
through the end of the study. Salivation was seen in a one canine in the 1X group on
Days 4 and 5, one canine in the 3X group on Days 2 and 3 and three canines in the 5X
group on Days 2 to 3 with one observation on Day 10. Lacrimation was seen in one
canine in the 3X group on Day 2. Miosis was observed in four canines in the 5X
group on Days 0 and 1.
Mean heart rates decreased in a dose-dependent manner for 2 days following dose
administration of the composition of the present invention and returned to rates
similar to that in the placebo group from Day 3 through 14. The maximal decrease in
heart rate was observed in the 5X dose group and was an approximately 50% decrease
relative to the placebo controls. Mean respiration rates were more variable than heart
rates, but they appeared to decrease slightly in a dose-dependent manner for 2 to 3
days after dose administration. However; unlike heart rate, the maximal decrease in
the mean respiration rate was similar in both the 3X and 5X dose groups at
approximately 30%. The mean rectal body temperatures decreased in a dose-
dependent manner, and remained below the placebo control in all treated dose groups
from 1 hour post-dose administration through Day 3 or 4. The maximum drop in
body temperature was approximately 2, 3 and 4° C on Day 1 in the 1X, 3X and 5X
groups, respectively.
Diffuse, bilateral ocular lens opacities were reported on Day 3 in one 3X canine and
three 5X canines by the attending veterinarian. A follow-up ophthalmic examination
was conducted on Day 7 by the attending veterinarian and the ocular opacities were
limited to one 3X group canine. A board-certified veterinary ophthalmologist was
consulted to examine the canines on Day 8 and the Day 7 findings were confirmed by
biomicroscopy following pharmacologic mydriasis. By Day 13, the lens opacities
were not observed in the single 3X canine as confirmed by a veterinary
ophthalmologist.
There were no arrhythmias or altered cardiac indices from the ECGs recorded on
Days 3 and 13. All mean hematology and serum chemistry results remained within
the normal range (see Tables 17, 18, and 19). The mean blood urea nitrogen (BUN)
on Day 3 in both the 3X and 5X groups increased to 14.2 and 13.2 mg/dL,
respectively but remained within the normal range. By Day 14, the BUN in both the
3X and 5X group were similar to Day -7 values. There were no necropsy or
histopathology findings considered to be related to fentanyl treatment. There were no
gross or microscopic evidence of abnormalities at the skin application site. There
were no gross or microscopic evidence of abnormalities in the eyes of the four canines
in the 3X and 5X groups that were observed with lens opacities over the first 7 days
of the study.
Table 17. Mean red blood cell and platelet parameters by dose group (n = 6 per
group) vs. time.
Parameter Day Control 1X 3X 5X
-7 6.34 6.45 6.42 6.17
Red blood cells
3 5.91 6.55 6.76 6.30
(10 /μL)
14 5.67 5.54 5.59 5.07
-7 14.7 15.0 15.1 14.4
Hemoglobin
3 13.6 15.2 15.9 14.8
(g/dL)
14 12.8 12.6 12.8 11.6
-7 43.6 44.8 44.9 42.8
Hematocrit
3 40.8 45.6 46.9 44.0
14 38.7 38.0 38.4 34.7
-7 68.8 69.5 69.9 69.5
3 69.0 69.6 69.3 69.9
(fL)
14 68.2 68.7 68.8 68.5
-7 23.1 23.3 23.5 23.3
3 23.0 23.2 23.5 23.4
(pg)
14 22.6 22.7 23.0 22.8
-7 33.6 33.5 33.6 33.6
MCHC
3 33.3 33.4 33.8 33.6
(g/dL)
14 33.2 33.1 33.4 33.4
-7 0.200 0.250 0.300 0.200
Reticulocytes
3 0.667 0.583 0.500 0.667
14 0.783 0.667 1.067 1.050
-7 14.0 13.6 13.6 13.2
3 14.1 13.5 13.6 13.2
14 14.3 13.9 14.0 13.7
-7 404 363 433 383
Platelets
3 337 327 394 322
(10 /μL)
14 328 292 367 313
MCV: Mean corpuscular volume; MCH: Mean corpuscular hemoglobin; MCHC:
Mean corpuscular hemoglobin concentration; RDW: Red cell distribution width.
Table 18. Mean white blood cell parameters by dose group (n = 6 per group) vs.
time.
Parameter Day Control 1X 3X 5X
-7 9.66 13.2 13.3 14.6
White Blood
Cells
3 8.61 11.7 16.9 16.5
(10 /μL)
14 7.96 8.02 10.6 13.0
-7 4.97 7.32 7.93 7.94
Neutrophils
3 3.97 7.24 12.1 12.5
(10 /μL)
14 3.88 3.79 5.72 8.08
-7 3.22 3.77 3.73 3.91
Lymphocytes
3 3.21 3.09 3.12 2.50
(10 /μL)
14 2.93 2.95 2.94 2.83
-7 0.648 0.995 0.850 1.02
Monocytes
3 0.510 0.653 0.923 0.743
(10 /μL)
14 0.477 0.475 0.668 0.817
-7 0.670 0.900 0.617 1.49
Eosinophils
3 0.815 0.627 0.558 0.618
(10 /μL)
14 0.585 0.750 1.15 1.15
-7 0.0683 0.0933 0.0767 0.103
Basophils
3 0.0467 0.0367 0.0667 0.0300
(10 /μL)
14 0.0400 0.0283 0.0400 0.0317
Table 19. Mean serum chemistry parameters by dose group (n = 6 per group) vs.
time.
Parameter Day Control 1X 3X 5X
-7 149 149 149 150
Sodium
3 147 148 147 148
(mEq/L)
14 144 145 146 144
-7 5.13 5.12 5.52 5.18
Potassium
3 4.92 4.92 4.52 4.60
(mEq/L)
14 4.68 4.68 4.67 4.42
-7 115 114 115 115
Chloride
3 115 113 106 112
(mEq/L)
14 112 112 114 113
-7 11.1 11.1 11.1 11.1
Calcium
3 10.9 10.9 11.1 10.9
(mg/dL)
14 10.8 10.8 10.6 10.5
-7 7.82 7.57 7.57 7.50
Inorganic
Phosphorus 3 8.02 7.67 7.82 7.17
(mg/dL)
14 7.63 7.23 6.88 6.68
-7 7.00 7.00 7.00 8.17
3 6.17 8.50 14.2 13.2
(mg/dL)
14 7.33 7.83 6.00 7.50
-7 0.883 0.883 0.933 0.950
Creatinine
3 0.683 0.683 0.700 0.650
(mg/dL)
14 0.867 0.850 0.850 0.900
-7 21.2 19.0 18.5 20.3
3 24.7 22.8 18.7 18.8
(IU/L)
14 23.0 22.5 24.7 21.5
-7 16.3 17.2 17.7 20.3
3 17.7 16.8 13.7 10.7
(IU/L)
14 17.0 16.7 18.0 17.2
-7 142 120 125 122
3 146 135 131 127
(IU/L)
14 144 125 123 100
-7 0.117 0.133 0.150 0.167
Total Billirubin
3 0.183 0.183 0.217 0.183
(mg/dL)
14 0.133 0.150 0.100 0.117
-7 2.17 2.67 2.17 2.50
3 1.83 2.00 1.83 2.33
(IU/L)
14 1.50 2.33 2.17 2.00
-7 207 216 198 228
3 217 255 278 256
(IU/L)
14 164 165 150 120
-7 114 112 117 107
Glucose
3 118 117 124 137
(mg/dL)
14 120 116 116 115
-7 5.58 5.62 5.63 5.53
Total Protein
3 5.48 5.68 5.92 5.63
(g/dL)
14 5.53 5.40 5.12 5.12
-7 2.70 2.77 2.77 2.63
Albumin
3 2.75 2.90 2.88 2.72
(g/dL)
14 2.78 2.77 2.57 2.38
-7 2.88 2.85 2.87 2.90
3 2.73 2.78 3.03 2.92
Globulin
14 2.75 2.63 2.55 2.73
(g/dL)
3 1.02 1.05 0.967 0.933
14 1.02 1.05 1.00 0.900
-7 169 175 198 182
Cholesterol
3 167 169 226 200
(mg/dL)
14 161 161 173 176
BUN: Blood urea nitrogen; ALT: Alanine aminotransferase; AST: Aspartate
aminotransderase; ALP: Alkaline phosphatase; GGT: Gamma glutamyltransferase;
CK: Creatine phosphokinase; A/G: Albumin to globulin ratio
Adverse reactions in the 1X group were transient and included a low incidence of
mild sedation, reduced food intake, modest weight loss and minimal reductions in
heart rate and rectal temperature. Moderate to severe sedation emerged in the 3X and
5X groups that was associated with a dose limiting reduction in food and water intake,
necessitating maintenance fluid replacement for the first two days following
application. Also observed in the higher dose groups were an increased incidence of
abnormal stools and transient lens opacities.
Sedation is an expected extension of the pharmacological effect of opioids. Mild
sedation was observed sporadically in some canines in the 1X dose group over 48
hours and with a greater magnitude and duration in the 3X and 5X groups. These
observations are consistent with previous reports where sedation increased with
plasma fentanyl concentrations when parenterally administered. Sedation has been
reported in canines following fentanyl transdermal patch application as well when
used at the recommended dose. At the higher doses of the composition of the present
invention (i.e., 3X and 5X) used in this study, sedation was a dose limiting adverse
event in that it resulted in lack of food and water intake requiring maintenance fluid
replacement over 2 days. This was unlikely the result of nausea as the emesis rate
was no different in placebo- and fentanyl-treated canines. In the 5X group, food
intake was eliminated altogether over 48 hours with a gradual return to baseline over
7 days. Food intake was sufficiently suppressed to cause a modest decrease in mean
bodyweight. Inappetence has been described with fentanyl administration and the
reduction in food intake may be a direct result of the drug, independent of sedation. A
surgical standard of care is that canines are typically fasted prior to surgery and are
gradually offered increasing quantities of food over time post-operatively depending
on the disease that necessitated surgery. Fentanyl-induced reduced food intake may
be superimposed on these post-operative care practices resulting in an under
awareness of this outcome.
The reversible bilateral lens opacities observed in one 3X and three 5X group canines
on Days 3 and 7 were likely due to corneal drying caused by prolonged moderate to
severe sedation. Although not reported in canines, this change has been observed in
rats that were anesthetized or that had corneal drying for any reason. In such cases,
the lens fibers along the posterior suture swell because of slight osmotic changes in
the cornea which somehow affect the aqueous and ultimately the lens. These changes
are not cataracts because they are reversible. However, the changes can become
irreversible if the condition(s) causing corneal drying are left unchecked. It was
therefore considered likely that the extended sedation associated with 3X and 5X
dosing in the present study resulted in transient corneal and lens drying, which in turn
caused the reversible lens opacities. These conclusions are also supported by the lack
of histopathologic findings in the lens. Although not observed in the 1X group, a
prudent clinical practice is to use eye lubrication for a period of time until the normal
palpebral reflex has been established following anesthesia.
Hypoventilation and respiratory depression were not dose limiting adverse reactions
in this study. This adverse event has been described in humans in association with
patch-delivered fentanyl that has resulted in acute death. As a result, transdermal
patches are contraindicated for use in conjunction with surgery and necessitate prior
tolerance to opioids. This is clearly not the case with administration of the
composition of the present invention in canines. Reductions in respiratory rates were
transient and marginally dose-dependent with a maximum reduction in rate of
approximately 30% in the 3X and 5X groups over the first 48 hours. These
observations are further supported by fentanyl data in canines following injection and
patch transdermal delivery. Plasma fentanyl concentrations as high as approximately
80 ng/mL reduce the respiratory rate by only approximately 11 breaths/minute (50%)
in spontaneously breathing canines. Additionally, respiratory rate, oxygen
consumption, and blood gases (pCO , pO , and pH) do not change further as
concentrations increase above 100 ng/mL. Sustained steady-state plasma fentanyl
concentrations of approximately 2 ng/mL as delivered by a patch over 48 hours do not
cause postoperative hypoventilation a confirmed by blood gas analysis. When taken
together, there is no data to support the necessity of prior opioid tolerance or
contraindication with anesthesia for use of the composition of the present invention in
canines.
Mean heart rates decreased in a dose-dependent manner following administration of
the composition of the present invention. Reduced heart rates have been reported
with both parenteral and patch delivered fentanyl. At plasma fentanyl concentrations
of 15 ng/mL, heart rates decreased by approximately 35 beats/minute (50%) and
further decreases in heart rate were not observed when plasma fentanyl concentrations
exceeded 15 ng/mL. The mean C in the 5X group was 13.5 ng/mL and the
maximum drop in heart rate was approximately 50% at 24 hours following dose
application. There were no changes to cardiac indices nor were arrhythmias observed
in the present study consistent with previous reports.
Although reduced rectal temperature is discussed in general terms in the opioid
literature for canines, body temperature outcomes in conscious canines over time have
not been reported following fentanyl administration. Opioids appear to alter the
equilibrium point of the hypothalamic heat-regulatory mechanism resulting in reduced
body temperature. The mean rectal body temperatures in this study decreased in a
dose-dependent manner. In the 1X dose, a transient decrease in body temperature was
observed with a maximum drop of 2° C at 24 hours following dosing. In anesthetized
canines, mean rectal temperatures decreased 0.9° C 60 minutes into mastectomy when
an administered 5 µg/kg/minute CRI of fentanyl throughout surgery, an infusion rate
that overlaps with the 1X dose and was no different than placebo.
The appearance of abnormal feces that included discolored stools (dark or red),
diarrhea or mucoid feces increased with the dose of the composition of the present
invention over the 14 day study period. Abnormal feces in the 1X group was
infrequent and limited to Days 1-3 whereas in the 3X and 5X groups, abnormal feces
were more sporadic beginning at Day 4 through the end of the study. Opioids have
been reported to diminish small intestinal secretions and decrease colonic propulsive
peristaltic waves resulting in reduced, desiccated feces. The appearance of loose,
mucoid or dark stools later in the study in the 3X and 5X groups may be related to this
phenomenon or may be related to a return to feeding after marked food reduction.
All mean clinical pathology results remained within the normal range throughout the
study although the mean BUN on Day 3 in both the 3X and 5X groups increased
slightly from baseline. Creatinine did not show an increase in parallel with BUN and
there were no gross or histological lesions in the kidneys. This was most likely
associated with reduced water intake secondary to sedation that necessitated fluid
replacement. Simultaneous urine samples were not collected to confirm a pre-renal
association. Alternate possibilities are reduced urine output secondary to the release
of antidiuretic hormone (ADH). High doses of fentanyl have been shown to have
antidiuretic properties in the canine and are likely related to the release of ADH.
All abnormal health observations were completely resolved prior to necropsy on Day
14 and there were no histological abnormalities identified. These data support the
safe use of the 1X dose and describe the outcome of an overdose of up to 5X the dose
in the absence of opioid reversal.
In summary, the results from Example 6 demonstrate the margin of safety of
administration of the composition of the present invention in healthy, laboratory
canines when administered at 1X, 3X and 5X the proposed dose of 2.6 mg/kg (50
µL/kg).
EXAMPLE 7
Naloxone Reversal of the Narcotic Effects of an Overdose of a Fentanyl
Composition Administered to Canines
An intramuscular (IM) naloxone reversal regime to the narcotic side-effects of an
overdose of the composition of the present invention in canines can be evaluated.
Twenty-four healthy purpose bred laboratory beagle canines (12 males/12 females)
were administered a single 13 mg/kg dose (5X overdose) of the composition of the
present invention and randomized to 2 reversal regime treatment groups, 40 µg/kg (8
canines) or 160 µg/kg IM naloxone (16 canines). All canines were administered a
single approximately 5X (13.0 mg/kg) overdose of the composition of the present
invention (use dose of 2.7 mg/kg) to the ventral abdomen. Sixteen hours after
administration of the composition of the present invention, canines were administered
8 hourly IM naloxone administrations according to their treatment assignment. All
canines were sedated prior to naloxone administration.
The plasma naloxone and fentanyl concentrations are displayed in Table 20. Plasma
fentanyl concentrations were below the LLOQ prior to dosing in all canines and the
mean fentanyl concentrations ranged from 4.60 to 6.53 ng/ml across both groups from
16 through 24 hours following administration of a 5X overdose (13 mg/kg) of the
composition of the present invention. The plasma naloxone concentrations were also
below the LLOQ prior to IM naloxone dose administration in all canines. At 5
minutes following the fifth naloxone dose administration (20.083 hr), the plasma
naloxone concentrations were 10.4 ± 0.238 ng/ml and 34.7 ± 1.75 ng/ml in the 40 and
160 µg/kg IM naloxone dose groups (Group 1 and 2), respectively. At 24 hours, the
mean plasma naloxone concentrations had dropped substantially from the previous
peaks in both groups, consistent with its known short duration of action and rapid
clearance. No seizures or other adverse affects of naloxone administration were
observed in any canines.
Table 20. Plasma fentanyl and naloxone concentrations by IM naloxone
treatment group
Plasma Fentanyl Conc. (ng/mL) Plasma Naloxone Conc. (ng/mL)
Tim 40 µg/kg IM 160 µg/kg IM 40 µg/kg IM 160 µg/kg IM
e Naloxone Naloxone Naloxone Naloxone
(hr)
Mea S Mea S Mea Mea S
n D n D n n D
< < < <
0 LLO — LLO — LLO — LLO —
Q Q Q Q
1. 1.
16 4.60 5.46 LLO — LLO —
52 18
.0 2. 1. 0.6 7.
.92 5.80 10.4 34.7
83 47 43 72 02
2. 2. 0.5 3.
24 5.42 6.53 2.78 12.8
60 27 68 39
SD: Standard deviation; < LLOQ: Less than lower limit of quantification for all
subjects.
For unknown reasons, six canines were observed as sedated at the time of
administration of the composition of the present invention (0 hr). Following a 5X
overdose (13 mg/kg) of the composition of the present invention, all canines were
sedated prior to naloxone administration (i.e. at 14, 15, 15.917 hr). The
administration of either 40 or 160 µg/kg IM naloxone at hourly intervals reduced the
proportion of sedated canines. The mean proportion of sedated canines from 16
through 24 hours for group 1 and 2 was 0.698 and 0.438, respectively. Additionally,
all canines were determined to be sedated at least once from 16 through 24 hours in
both groups. The mean proportion of sedated canines returned to 1.0 following
cessation of the hourly IM naloxone administrations for both groups by 26 hours.
The overall effect of naloxone on reversal of the sedative effects of the composition of
the present invention was statistically significant (P < 0.001), as was the individual
effect of the 40 and 160 µg/kg IM naloxone reversal regimes (P < 0.001 for both
regimes). The analysis also indicated that there was significant subject-to-subject
variability in the sedation response (i.e. the probability that > 0 was < 0.05).
Furthermore, the narcotic reversal affect of the 160 µg/kg IM naloxone dose was
significantly greater than that for the 40 µg/kg IM naloxone dose (P = 0.0132). The
odds of a subject being sedated with a 160 µg/kg IM naloxone dose was 0.353 (95%
CI [0.0327-0.674]) fold that of a 40 µg/kg IM naloxone dose. Due to high degree of
40 160
β β β β
F N N F
correlation (near -1.00) between and , , the value of was fixed to the
initial estimate of 11.5. Varying the fixed value of from 1 to 30 had no affect on
the hypothesis test results (accurate numerical integration of the likelihood could not
be achieved for values of > 30), indicating the results are robust to different
reasonable fixed values of .
The rectal body temperatures across both groups dropped from 38.4 ± 0.0976 °C prior
to administration of the composition of the present invention to 35.1 ± 0.0884 °C
following treatment (i.e. at time 14, 15, and 15.917 hr). During IM naloxone reversal
(i.e. from 16 through 24 hr), the body temperature across both groups was 37.7 ±
0.0578 °C. By 26 and 28 hours the body temperatures returned to near pre-naloxone
administration values with an overall mean of 35.9 ± 0.0976 °C. The mean body
temperature during naloxone treatment time period ( ) was 2.19 ± 0.0638 °C higher
than the mean during the fentanyl only time period ( ) (P < 0.001). Additionally,
during the naloxone treatment time period the body temperature was 0.412 ± 0.123 °C
higher in the 160 µg/kg IM naloxone dose group than in the 40 µg/kg IM naloxone
dose group (P < 0.001), indicating greater narcotic reversal effect of the higher IM
naloxone dose.
The heart rates across both groups dropped from 101 ± 3.31 bpm prior to
administration of the composition of the present invention to 64.2 ± 3.04 bpm
following administration of the composition (i.e. at time 14, 15, and 15.917 hr).
During IM naloxone reversal (i.e. from 16 through 24 hr), the HR across both groups
returned to the pre-administration HR measurements with a value of 101 ± 2.41 bpm,
and then dropped again to an overall mean of 83.1 ± 3.31 bpm following termination
of naloxone administration. The mean HR during naloxone treatment time period
( ) was 28.9 ± 1.78 bpm higher than the mean during the fentanyl only time period
( ) (P < 0.001). Finally, during the naloxone treatment time period the HR was
9.97 ± 5.11 bpm higher in the 160 µg/kg IM naloxone dose group than in the 40
µg/kg IM naloxone dose group (P = 0.0258), further indicating greater narcotic
reversal effect of the 160 µg/kg IM naloxone dosage.
In summary, the narcotic side-effects of an overdose of the composition of the present
invention can be safely and effectively reversed by hourly administration of either 40
µg/kg or 160 µg/kg IM naloxone; however, the 160 µg/kg regime is more effective.
EXAMPLE 8
In Vitro and In Vivo Effect of Penetration Enhancer Following Transdermal
Administration of a Fentanyl Composition to Canines
The in vitro and in vivo effects of the penetration enhancer in the composition of the
present invention can be evaluated. In vitro effects can be assessed by applying a
fentanyl composition with a penetration enhancer and a fentanyl composition without
a penetration enhancer to cadaver skin. Thereafter, the effect of fentanyl flux across
the skin can be evaluated. In this experiment, octyl salicylate can be used as the
penetration enhancer. In vivo effects can be assessed by administering a single dose
of the fentanyl composition with a penetration enhancer and a single dose of the
fentanyl composition without a penetration enhancer to canines at a dorsal location.
Thereafter, the systemic blood level exposure of fentanyl in the canines can be
evaluated. In this experiment, octyl salicylate can be used as the penetration
enhancer.
In the in vivo experiment, Group 1 included twelve adult male beagle dogs
administered a single transdermal dose of a composition comprising fentanyl at a
concentration of 2.6 mg/kg (52 µL/kg) plus octyl salicylate. A second group (Group
2) included twelve adult male beagle dogs administered a single transdermal dose of a
composition comprising fentanyl at a concentration of 2.6 mg/kg (52 µL/kg) but
without octyl salicylate.
Blood samples for plasma fentanyl concentration determination were collected from
pre-dosing through 21 days post-dosing from all subjects. A deconvolution analysis
was conducted to determine the systemic absorption of fentanyl over time, and the
cumulative amount of fentanyl systemically absorbed at 21 days post-dosing was
statistically compared between the two treatment groups.
The summary statistics of the systemic fentanyl absorption rates for the two treatment
groups are displayed in Table 21. The mean systemic absorption rate was greater in
Group 1 than Group 2 at each sampling time point through 96 hours post-dosing,
indicating a substantial effect of octyl salicylate on the fentanyl absorption rate for the
first 96 hours after transdermal fentanyl solution administration. After 96 hours post-
dosing, the systemic fentanyl absorption rates were similar in both treatment groups.
Table 21. Systemic fentanyl absorption rate (mg/kg/hr) summary statistics by treatment group and time
Time (hours)
0 1 2 4 8 12 16 24 36 48 96 16 24 33 40 50
8 0 6 8 4
n 1 12 12 12 1 12 12 12 12 12 12 12 12 12 12 12
M 0 0. 0. 0. 0. 0. 0. 0. 0. 0. 0. 0. 0.0 0.0 0.0 0.0
G e . 00 00 00 0 00 00 00 00 00 00 00 01 01 00 00
0 64 30 89 2 42 87 76 75 73 50 25 62 27 80 66
o n 0 3 2 8 3 1 2 7 4 6 1 1 1 7
p S 0 0. 0. 0. 0. 0. 0. 0. 0. 0. 0. 0. 0.0 0.0 0.0 0.0
1 D . 00 00 00 0 00 00 00 00 00 00 00 00 00 00 00
0 75 25 70 2 38 23 28 26 33 33 22 43 78 48 64
0 6 5 0 2 0 6 3 9 5 1 6 6 4 0 2
n 1 12 12 12 1 12 12 12 12 12 12 12 12 12 12 12
M 0 0. 0. 0. 0. 0. 0. 0. 0. 0. 0. 0. 0.0 0.0 0.0 0.0
G e . 00 00 00 0 00 00 00 00 00 00 00 01 01 00 00
r a 0 31 16 43 1 10 37 40 21 35 26 26 84 48 93 62
0 9 3 0 4 8 7 1 8 3 6 3 5 9
S 0 0. 0. 0. 0. 0. 0. 0. 0. 0. 0. 0. 0.0 0.0 0.0 0.0
2 D . 00 00 00 0 00 00 00 00 00 00 00 00 00 00 00
0 23 18 45 1 12 29 37 11 18 10 13 74 54 36 44
0 8 6 6 5 1 4 6 1 9 5 1 1 3 0 1
SD: Standard Deviation
The summary statistics of the cumulative systemic fentanyl absorption for the two
treatment groups are displayed in Table 22. The cumulative systemic absorption at 48
hours post-dosing were 0.413 ± 0.168 (mean ± SD) and 0.193 ± 0.0943 mg/kg in
Group 1 and Group 2, respectively. Similarly, the cumulative systemic absorption
amounts at 96 hours post-dosing were 0.706 ± 0.272 and 0.342 ± 0.126 mg/kg in
Group 1 and Group 2, respectively. Thus, at 48 and 96 hours post-dosing, over twice
as much fentanyl was systemically absorbed in dogs administered transdermal
fentanyl solution containing octyl salicylate than in dogs administered transdermal
fentanyl solution without octyl salicylate. At 21 days (504 hours) post-dosing the
cumulative systemic absorption was 1.40-fold higher in Group 1 than in Group 2 at
1.41 ± 0.550 and 1.01 ± 0.260 mg/kg, respectively. This difference in cumulative
systemic absorption was statistically significant (P < 0.05).
Table 22. Cumulative systemic fentanyl absorption (mg/kg) summary statistics by treatment group and time
Time (hours)
0 1 2 4 8 12 16 24 36 48 9 1 2 3 4 5
6 6 4 3 0 0
8 0 6 8 4
n 1 12 12 12 12 12 12 12 12 12 1 1 1 1 1 1
2 2 2 2 2 2 2
0 0.0 0.0 0.0 0. 0. 0. 0. 0. 0. 0. 0. 1. 1. 1. 1.
Gr ea . 012 079 189 08 14 16 23 32 41 7 9 1 2 3 4
ou n 0 2 3 45 2 6 3 3 3 0 8 3 6 4 1
p 0 6 5
1 S 0 0.0 0.0 0.0 0. 0. 0. 0. 0. 0. 0. 0. 0. 0. 0. 0.
D . 013 043 086 06 10 10 11 14 16 2 4 5 5 5 5
0 5 0 5 31 7 6 9 3 8 7 5 2 3 4 5
0 2 8 7 7 5 0
n 1 12 12 12 12 12 12 12 12 12 1 1 1 1 1 1
2 2 2 2 2 2 2
M 0 0.0 0.0 0.0 0. 0. 0. 0. 0. 0. 0. 0. 0. 0. 0. 1.
Gr ea . 065 087 133 05 08 09 12 15 19 3 5 6 8 9 0
0 5 1 03 10 01 2 9 3 4 3 9 5 4 1
ou n
p 0 2 3 4 3 0
S 0 0.0 0.0 0.0 0. 0. 0. 0. 0. 0. 0. 0. 0. 0. 0. 0.
D . 130 125 120 04 07 07 07 08 09 1 1 1 2 2 2
0 19 14 14 57 48 43 2 6 9 2 4 6
0 6 0 9 1 0 0
SD: Standard Deviation
In summary, the mean systemic fentanyl absorption rates were greater through 96
hours post-dosing in dogs that received transdermal fentanyl solution containing octyl
salicylate than in dogs that received transdermal fentanyl solution without octyl
salicylate. Likewise, at 21 days post-dosing, the mean cumulative amount of
systemically absorbed fentanyl was 1.40-fold higher (P < 0.05) in dogs that received
the transdermal fentanyl solution containing octyl salicylate. Thus, the penetration
enhancer octyl salicylate increased both the rate and extent of systemic fentanyl
absorption following a single topical administration of transdermal fentanyl solution
to the dorsal inter-scapular region in dogs.
EXAMPLE 9
Effect of Wetting on the Amount of Topical Residual Fentanyl Wiped
from the Application Site Following Transdermal Administration of a Fentanyl
Composition to Canines
The effects of wetting the application site in canines following transdermal
administration of the composition of the present invention can be evaluated. The
evaluation can be performed by measuring the amount of residual fentanyl wiped
from the topical application site of canines following a single administration of the
composition of the present invention. Canines can be randomized to 1 of 10 treatment
groups (4 canines per group). The application site (dorsal, inter-scapular region) of
all canines can be wiped with a cotton glove on Day -1 to confirm that no fentanyl is
present prior to dose administration. Canines in five of the treatment groups (i.e.,
Groups 1W-5W) can have the application site wetted with distilled water (via a spray
bottle) approximately 5 minutes prior to cotton glove wiping. Canines in the other
five treatment groups (i.e., Groups 1D-5D) can have the application site remain dry
prior to cotton glove wiping. A single approximately 2.7 mg/kg (~54 µL/kg) topical
dose of the composition of the present invention can be applied to the dorsal,
interscapular region to all canines on Day 0. A second cotton glove wiping (wet or
dry) can be conducted for each canine post-dosing according to the treatment
randomization. Groups 1D and 1W canines can be wiped on Day 0 at 8 hours post-
dose administration. Canines in Groups 2D/W, 3D/W, 4D/W, and 5D/W can be
wiped at 24, 48, 72, and 120 hours postdose administration, respectively. Cotton
gloves can be assayed for fentanyl amounts using a validated analytical method.
Summary statistics of the residual fentanyl amounts per glove, normalized for
bodyweight, can be calculated by time and dry/wet application site. The effect of
wetting the application site on the normalized residual fentanyl amounts can also be
analyzed.
In the present example, 40 beagle canines were randomized to one of the ten
treatment groups (4 canines per group). Table 23 shows the residual fentanyl amount
(µg/kg of bodyweight) detected on cotton gloves for each treatment group. Fentanyl
was not measureable (i.e., measurements were below the lower limit of quantification)
on any of the pre-dose administration (Day -1) cotton glove samples. At 8 hours post-
dosing, the mean residual fentanyl amounts recovered from the cotton gloves were
41.0 and 35.4 µg/kg of bodyweight with dry and wet application sites, respectively.
As a percent of the nominal 2.7 mg/kg transdermal fentanyl solution dose, the mean
residual fentanyl amounts were 1.52% and 1.31%, respectively. At 72 hours post-
dosing, mean cotton glove residual amounts were 0.31% and 0.35% of the applied
dose for dry and wet application sites, respectively; and at 120 hours post-dosing, the
mean residual amounts were < 0.28% and 0.19%, respectively.
Table 23. Residual fentanyl amount (µg/kg of body weight) detected on cotton
gloves by nominal wiping time and dry or wet application site
Application Time Post-Dosing (hours)
Site
0 8 21 48 72 120
4 4 4 4 4
Dry N
Mean <LLOQ 41.0 20.7 20.4 8.46 <7.50
SD NC 12.1 6.87 6.11 2.31 4.80
Wet N 20 4 4 4 4 4
<LLOQ 35.4 15.2 20.5 9.49 5.12
Mean
SD NC 21.5 9.11 15.8 4.56 1.98
< LLOQ: less than the lower limit of quantification (20 µg); NC: not calculable; SD:
Standard Deviation
A linear fixed effects model analysis indicated no statistically significant main effect
of the dry versus wet application site on residual fentanyl amounts (p = 0.4568) and
no statistically significant interaction effect between the dry/wet application site and
time post-dosing (p= 0.9485). Thus, it appears that wetting the application site had no
effect on the amount of topical residual fentanyl wiped from the application site with
a cotton glove following a single administration of transdermal fentanyl solution to
canines.
No animals were removed and no deaths occurred during the study. Seven adverse
events occurred during the study. All adverse events occurred on Day 1 or 2 of the
study and involved vomiting or vomiting and inappetance. The adverse events were
categorized as mild and possibly related to fentanyl treatment. No medical
interventions were required.
The term “comprising” as used in this specification and claims means “consisting at
least in part of”. When interpreting statements in this specification and claims which
include the term “comprising”, other features besides the features prefaced by this
term in each statement can also be present. Related terms such as “comprise”,
“comprises”, and “comprised” are to be interpreted in similar manner.
In this specification where reference has been made to patent specifications, other
external documents, or other sources of information, this is generally for the purpose
of providing a context for discussing the features of the invention. Unless specifically
stated otherwise, reference to such external documents is not to be construed as an
admission that such documents, or such sources of information, in any jurisdiction,
are prior art, or form part of the common general knowledge in the art.